A nasal device for use in drug delivery via the nasal cavity

Abstract

The disclosure relates to a nasal device for delivery of pharmaceutical substances, the nasal device being adapted for insertion into a nostril of a human subject, wherein the nasal device comprises a structural molded material and a composition comprising at least one pharmaceutical substance, said composition being evenly dispersed in the structural molded material.

Description

[0001] A nasal device for use in drug delivery via the nasal cavity

[0002] Technical field

[0003] The present disclosure relates to a nasal device for use in delivery of pharmaceutical substances, a pharmaceutical composition comprising at least one pharmaceutical substance for use in such a nasal device, and related methods, as defined in the introductory parts of the independent claims.

[0004] Background art

[0005] Current methods of drug delivery have various drawbacks. For example, many drugs are delivered in high doses via injections, pills, capsules etc., as the method of delivery, especially via the bloodstream, is not efficient. Thus, a large part of the administered drug never reaches the intended target site, leading to an unnecessary stress on various organs, such as the liver. Further, unnecessary cost and environmental impact is accumulated for producing and supplying an excessive amount of the drug that will not be used. Moreover, there are issues with regard to the efficiency and compatibility of presently used methods and devices.

[0006] Hence, there is a need for improved devices and drug delivery protocols using such devices for improving the outcome of administration of drugs.

[0007] WO2011 / 162677A1 describes a nose plug adapted for insertion into the nasal cavity. WO2018206388A1 discloses another nasal device adapted for placement in the nostril opening.

[0008] Summary

[0009] It is an object of the present disclosure to mitigate, alleviate or eliminate one or more of the above-identified deficiencies and disadvantages in the prior art and solve at least the above mentioned problem.

[0010] The present inventors have surprisingly found that a nose plug or nasal device and / or a plurality of such nasal devices, for example structurally configured substantially as described in either WO2011 / 162677 or WO2018 / 206388 (both incorporated by reference herein), further comprising at least one composition, said composition comprising at least one pharmaceutical substance, may be used for efficient drug delivery via the nasal cavities. The nasal devices and methods described herein are especially suitable for delivery to the central nervous system, including the brain.

[0011] Therefore, according to a first aspect there is provided a nasal device for use in a delivery of pharmaceutical substance, the nasal device being adapted for insertion into a nostril of a human subject, wherein the nasal device comprises a structural molded material and at least one composition. The composition comprises at least one pharmaceutical substance, and optionally other components such as a solvent, auxiliary substances and / or excipients. Further, the composition is evenly dispersed in the structural molded material. The composition is composed to essentially maintain the pharmaceutical properties of the pharmaceutical substance during a production process for the nasal device, the process comprising heating to a temperature of at least about 150°C. The substance is adapted to be released in gaseous form from the nasal device at a rate and duration suitable for administration of the substance via the olfactory bulb, the trigeminal nerve, upper airways, nasal mucosa and / or a combination thereof. Therefore, as unique features of the present disclosure, and especially relevant for small molecule drugs (as is part of most pharmaceuticals) a slow release and / or a sustained release can be obtained, in contrast to administration by injection, tablets or spray. Also, by administering the pharmaceutical substance in gaseous form from the nasal device, no carrier is needed, as would otherwise often be the case, e.g. when using a nasal spray or an inhalator. Thus, the pharmaceutical substance in gaseous form can be set free by diffusion from the nasal device. This has been shown herein to enable the substance to more easily be captured in the nasal cavity itself, and especially the regions near and at the olfactory bulb and trigeminal nerve, which enables the substance to more easily reach the central nervous system.

[0012] In one aspect, the composition, or the substance comprised in the composition, exhibits a flashpoint of at least about 150 °C, or for protein substances at least about 60 °C. A high flashpoint ensures that the pharmaceutical substance in the composition can maintain its pharmaceutical properties. The flashpoint of the composition is not necessarily the same as the flashpoint of the pharmaceutical substance in the composition but could be influenced by the other components in the composition. Thus, by adjusting the ratio and presence of other components in the composition, a more suitable flashpoint can be achieved. The flashpoint is in some cases also influenced by the fact of the composition being mixed into the structural molded material. In other words, the structural molded material may have a protective effect on the pharmaceutical substance or the entire composition in that the combination of structural molded material and composition can handle a higher production temperature than the substance or composition itself.

[0013] In another aspect, at least one of the composition as a whole and the pharmaceutical substance comprised in the composition exhibits a vapor pressure of at least 0.001 + / - 0,0005 mmHg at 25 °C. Once the nasal device is placed in the user's nostril, the pharmaceutical substance and / or the composition will be released in a gaseous form from the nasal device, such that it enters the inhaled air of the user and is transported into the nasal cavity to the olfactory bulb, the trigeminal nerve, upper airways, nasal mucosa and / or lungs. Notably, the term "gaseous form" entails that the pharmaceutical substance is in a gas phase, or in some cases in a finely diffused form. This differs significantly from a nasal spray, wherein a substance is delivered in a liquid carrier and / or liquid droplets, or from an inhaler, wherein a substance may be delivered as a liquid, a salt or a powder, typically together with a carrier.

[0014] These modes of delivery enable the pharmaceutical substance to be easily absorbed and distributed directly to the central nervous system, which is primarily achieved by distribution via the olfactory bulb and / or the trigeminal nerve. This opens up new administration possibilities for treatment of diseases and conditions that may lack adequate administration routes.

[0015] Known nasal delivery methods include nasal sprays, applied via a liquid spray, or dry powders, applied via inhalers. Such routes result in a majority of the applied dose ending up in the airways and lungs, and absorbed through the various membranes. Similar to pills, plasters or injection, such delivery modes entail uptake and transport via the blood, and are to a large extent hindered to access the central nervous system by the blood-brain barrier. In some aspects, the composition comprises essentially only the pharmaceutical substance. In some aspects, the pharmaceutical substance alone is mixed with the structural molded material to form the nasal device.

[0016] In some aspects, the composition is comprised in an oil-like or liquid form in the structural molded material. "Oil-like form" is herein defined to comprise substances that in themselves exhibit properties similar to that of an oil, such as biocompatibility, suitable viscosity, preferably smell-free, etc. In addition, "oil-like form" also comprises substances in any oil-based or organic solvent that has properties similar to that of an oil, such as biocompatibility, suitable viscosity, preferably smell-free, etc. An example of a substance with oil-like form is essentially pure nicotine in its neat liquid state, C10H14N2, CAS number 54-11- 5. For example, using nicotine or menthol in its fluid state has proven effective in the nasal device disclosed herein. See also the Examples included herein for additional substances.

[0017] In some aspects, the pharmaceutical substance of the composition has any of the following characteristics: a. it is in liquid form upon mixing with the material of the nasal device to be molded; or b. it is in solid form, such as a powder, and the composition, in which it is comprised in, is in liquid form, upon mixing with the material of the nasal device to be molded.

[0018] Therefore, when the pharmaceutical substance is in solid form and / or for other reasons need to be included in a composition comprising other components, such as a solvent, auxiliary substances and / or excipients, it is important that the resulting composition exhibits the properties that are necessary for retaining the pharmaceutical properties of the pharmaceutical substance during the production process of the nasal device, and for the pharmaceutical substance to be released from the nasal device when used. For example, this can be obtained by mixing and / or dissolving a pharmaceutical substance in solid form with a liquid, such as an oil, to be incorporated in the nasal device material. The liquid and / or oil to be used a solvent should have the ability to diffuse out from the nasal device material. Thus, the liquid and / or oil to be used as a solvent for a pharmaceutical substance in solid form could be hydrophobic and / or lipophilic. For example, commercially available synthetic or vegetable oil can be used for this purpose. Other auxiliary substances and / or excipients can also be included to facilitate that the pharmaceutical substance maintains its pharmaceutical properties during the production process and is releasable in gaseous form from the nasal device during use.

[0019] Using a liquid form of composition for mixing into the structural material is advantageous in regards to the ease of dispersing the composition in the structural material, and further may be advantageous to obtain a final product wherein the substance is released from the nasal device over a longer period of time, i.e. so called slow release.

[0020] In some aspects, the composition has a melting point lower than about 100 degrees °C preferably lower than about 80 °C. Using a composition having a low melting point makes it easier to mix into the structural material and ensuring even distribution of the composition in the nasal device.

[0021] In some aspects, the pharmaceutical substance has a molecular mass within the interval of 50 to 10.000 g / mol. The molecular mass of a substance typically has an effect on other parameters, and e.g. a high molecular mass is often associated with a higher melting point and a lower vapor pressure.

[0022] In some aspects, the pharmaceutical substance has a molecular mass within the interval of 50 to 750 g / mol. In other aspects, the pharmaceutical substance has a molecular mass within the interval of 750 to 10.000 g / mol. Thus, pharmaceutical substances for use in the present invention can broadly be grouped in a first group of low to medium molecular mass (lower than 750 g / mol) and a second group of medium to high molecular mass (higher than 750 g / mol), wherein the first group typically includes small molecules and the second group larger and / or more complex molecules. Typically, small molecules will more easily diffuse out from the product and will more easily be transported over the olfactory bulb and / or the trigeminal nerve. The larger and / or more complex molecules will typically be more difficult to be delivered into the body in their pure form, but can typically provide a more complex treatment. Thus, depending on type of substance and molecule type and size, the delivery of the substance to the body via the olfactory bulb, trigeminal nerve, upper airways, nasal mucosa or lungs to enter the central nervous system directly and / or the blood stream to reach inner organs may be different, which is to be taken into account when optimizing the composition that the pharmaceutical substance is comprised in (and / or if the pharmaceutical substance is essentially the only component of the composition). The nasal device of the present disclosure therefore presents an improved way of delivering pharmaceutical substances to the body, and is suitable for delivery of a large variety of pharmaceutical substances.

[0023] In some aspects, the pharmaceutical substance has a polar surface area within the interval of 50-500 A2, or 10-200 A2. The polar surface area of a substance plays a significant role in its ability to cross biological membranes, and thus affects the transport of the substance to its intended target site. The polar surface area of a substance thus affects its absorption, distribution, and overall effectiveness in the body. Using a substance with a polar surface area within the interval as described herein has proven to have an optimal balance of bioavailability and distribution, such that the substance reaches the target site most effectively, especially for target sites within the central nervous system. Typically, a bodily membrane (such as one to be crossed by a pharmaceutical substance according to this disclosure) is mucosal on one side and blood / plasma on the other side. For a substance to cross the membrane, it must be dissolved in both sides. Thus, the polarity should be about 1-5 logP, i.e. a "medium" value. For crossing into the CNS, a polar surface area of about 80-120 is typically an optimum, whereas for pharmaceutical substances crossing membranes in general, a broader interval is typically valid.

[0024] Overcoming the difficulty of delivering therapeutic agents to specific regions of the brain thus presents a major challenge to treatment of most brain disorders. Nose-to-brain delivery has emerged as a promising non-invasive route to drug administration. It appears to be a complex process in several steps, and most likely using several complementary distribution pathways and transport mechanisms. The present disclosure describes a device and related methods to deliver pharmaceutical substances primarily to the brain and the central nervous system. The nasal devices disclosed herein are intended for quick / immediate and / or slow release of the one or more substances over time, and for delivery via the olfactory bulb pathway and / or the trigeminal nerve pathway, in some aspects also in combination with via the airways, lungs and membranes of the nasal cavity. In preferred aspects, the substance is released from the nasal device into the air flow, i.e. the air being inhaled by a user, and thereby reaches far into the nasal cavity. Some of the substance is likely taken up by the mucous membranes in the nasal cavity, airways and the lungs, and may enter the bloodstream and / or bypass the blood-brain barrier, depending on the substance and its intended use. However, a substantial amount of the released substance appears to be delivered through neural connections among the olfactory epithelium, olfactory bulb, trigeminal nerve, and the brain. Typically, at least a significant portion, such as at least 30%, of the administered substance therefore bypasses the blood brain barrier and quickly affects the central nervous system, including the brain, resulting in a quicker effect after administering a drug to a patient. This is advantageous compared to other administration routes, and also allows for lower dosages to be given compared to other delivery methods. The body can take up and effectively use a larger part of the dose given, and a smaller dose can thus be administered. This is an advantage as there is less stress on the body's different organs involved in transport and degradation of foreign substances. Further, there may also be a positive environmental effect, as less harmful chemicals end up in the environment.

[0025] Moreover, the present nasal devices provide a quicker effect of the drug once applied to the patient, as compared to traditional routes. It also provides the possibility of being able to change dosage over time, while also being able to administer a substance in a controlled manner over a longer period of time. In addition, one avoids having the substance pass through the liver, such as when a pharmaceutical is delivered via the bloodstream, and a better liver health is obtained in the user. Thus, the present solution results in a more cost efficient substance delivery, as less is lost during transmission to the target site, due to not having to pass through blood-brain barrier and the liver. Further, better control over a longer time period is achieved.

[0026] In some aspects, the nasal device as described herein is adapted for use in delivery of the pharmaceutical substance, wherein the pharmaceutical substance is released in gaseous form from the nasal device and is primarily intended to be delivered to a target site in the body via the olfactory bulb, the trigeminal nerve, upper airways, nasal mucosa and / or a combination thereof. In some aspects, the target site is in the central nervous system. The nasal device described herein has proven to be an advantageous manner of delivering a pharmaceutical substance to the central nervous system, including the brain, by delivering the substance via primarily the olfactory bulb to the brain and other parts of the central nervous system.

[0027] The nasal device as described herein, and delivery of a pharmaceutical substance as described herein, may be used for any of the following applications: neonatal drug delivery, catastrophic medicine delivery, for patients having a neurodegenerative disease, for malnourished patients, cancer patients, patients in need of pain relief, patients in elderly care (which patients may have difficulties to swallow orally administered pills), patients having pinprick fear or fear for syringes (such as trypophobia), to avoid risk of overdosing the pharmaceutical substance and in general as an alternative to using needles / syringes, pills, nasal spray or other types of formulations.

[0028] For example, in catastrophic medicine or emergency care, the substance to be delivered may be an antidote towards an overdose or to counteract toxicity of various kinds. Another example is when a patient is malnourished, severely injured, uncooperative or unresponsive, delivering a pharmaceutical substance via the nasal delivery route makes for easier administration, and in many cases, it may be advantageous to quickly reach the central nervous system as described herein. As the delivery via the presently disclosed manner has a long-term effect as well as a continuous dosage, without being invasive or disturbing to the patient, it is especially useful for delivery of e.g. sleep medications, pain medications, and in addition treatment. It also is advantageous when a patient exhibits liver problems, as the delivery bypasses the liver to a large extent. The direct route to the central nervous system is further advantageous when treating diseases in the central nervous system, such as brain cancer, Alzheimer's disease, neurodegenerative diseases, epilepsy etc. Another application where a direct route is advantageous is in treatment of obesity, where receptors in the brain are the intended target.

[0029] As described above, delivery via a nasal device as described herein has the potential combined effect of an initial quick effect combined with a slow release over a longer time period. Alternatively, only an initial quick effect or a slow-release effect may be obtained. Known delivery methods, such as via an intravenous needle, a pill or capsule, or via a spray (such as a nasal spray or a transdermal spray), an inhaler or a patch, all offer either one or the other, but not both. Further, there is a practical aspect of delivering via a non-invasive and user-friendly manner of inserting a nasal device into the patients nostril. For instance, it requires no effort of the patient him- or herself, and may be performed on an unresponsive, scared or uncooperative patient.

[0030] In some aspects, the pharmaceutical substance is evenly dispersed in a structural molded material of the nasal device and comprises one or more of L-Dopa, codeine, oxytocin, lorazepam, desogestrel, progesterone, rimantadine, noxytiolin, L-(-)-menthol, dexfenfluramine, anethol, pentorex, fenfluramine, fomepizole, valproic acid, memantine, nicotine, iron, vitamins such as B12, cytizine, morphine, fentanyl, triptans, various vaccines, adrenaline, amphetamine, Zyprexa (olanzapine), carbamazepine, azelastine, fluticasonpropionate, mometasone, naloxone, xylometazoline, apomorphine, or any substance effective on the central nervous system, including anesthetics, anticonvulsants, antiemetics, anti-Parkinson agents, CNS stimulants, muscle relaxants, narcotic analgesics (pain relievers), nonnarcotic analgesics (such as acetaminophen and NSAIDs), and sedatives.

[0031] Typically, the pharmaceutical substance(s) to be used for the purposes of this disclosure is chosen from any of the following groups of molecules: lipids, proteins, carbohydrates, nucleic acids (micro-RNA, RNA or DNA), peptides and small molecules. Other molecule types having a pharmaceutical effect are also conceivable.

[0032] In some aspects, the pharmaceutical substance is comprised in the nasal device at a dosage of 0.01 to 500 mg per nasal device, or from 0.1 to 50 mg per nasal device. Such nasal devices have been shown to be effective in delivering several pharmaceutical substances to a desired target site via in vitro simulated pathways corresponding to the delivery pathways via the olfactory bulb, the trigeminal nerve, upper airways, and nasal mucosa, as illustrated in the Examples disclosed herein. It is proposed that delivery via two or more of such pathways has a combinatory effect of being more effective and contributes to an initial peak amount of delivered substance after an initial short period of time combined with a slow release at a lower dosage over a longer period of time, such as 8, 24 or 48 hours. This results in a more efficient delivery to and resulting effect on the central nervous system. For example, a quick effect could be obtained by delivery of part of the substance (such as 50%) via the olfactory bulb or the trigeminal nerve directly to the CNS, and a slower effect by delivery of part of the substance (such as 50%) to bodily organs via the blood stream, e.g. entering the blood stream via airways, lungs or mucosa.

[0033] According to some aspects, the nasal device comprises a plurality of pharmaceutical substances, wherein the plurality of pharmaceutical substances are either comprised in the same composition, or are comprised in separate compositions. Thus, a plurality of compositions comprising at least one pharmaceutical substance can be used for simultaneous, overlapping or sequential delivery, as long as the compositions can be incorporated in the structural molded material of the nasal device, and the composition is suitable for nasal delivery. Accordingly, the plurality of pharmaceutical substances can have different properties, thereby being able to be included essentially directly in the nasal device material and / or being comprised in a composition comprising a liquid and / or oil, as long as each pharmaceutical substance included in the nasal device has the ability to maintain its pharmaceutical properties during the production process and be releasable in gaseous form from the nasal device when used. Hereby, a combinatory therapeutical effect, including the pharmaceutical effects of each of the pharmaceutical substances, is obtained when the nasal device is used by a subject.

[0034] Further is provided a method for administration of a pharmaceutical composition comprising at least one pharmaceutical substance to a target site in the body of a subject via the olfactory bulb, the trigeminal nerve, upper airways, nasal mucosa, lungs and / or a combination thereof, wherein the pharmaceutical substance is released in gaseous form from a nasal device as described herein.

[0035] In some aspects, in the method above, the pharmaceutical substance comprises one or more of L-Dopa, codeine, oxytocin, lorazepam, desogestrel, progesterone, rimantadine, noxytiolin, L-(-)-menthol, dexfenfluramine, anethol, pentorex, fenfluramine, fomepizole, valproic acid, memantine, nicotine, iron, vitamins such as B12, cytizine, morphine, fentanyl, triptans, various vaccines, adrenaline, amphetamine, Zyprexa (olanzapine), carbamazepine, azelastine, fluticasonpropionate, mometasone, naloxone, xylometazoline, apomorphine, or any substance effective on the central nervous system, including anesthetics, anticonvulsants, antiemetics, anti-Parkinson agents, CNS stimulants, muscle relaxants, narcotic analgesics (pain relievers), nonnarcotic analgesics (such as acetaminophen and NSAIDs), and sedatives.

[0036] In some aspects, in the method above, the pharmaceutical substance is provided so that a combinatory effect is obtained, wherein a quick effect is obtained by delivery via the olfactory bulb and / or the trigeminal nerve to the central nervous system, and a slow release effect is obtained by delivery via the upper airways, nasal mucosa and / or lungs to the blood stream and subsequently to bodily organs.

[0037] In some aspects, in the method above, the pharmaceutical substance, upon administration to a subject, exhibits an immediate peak output rate, measured after about 10 minutes - 2 hours, at its target site in the subject, and a slow-release output rate, measured at some point in time after a duration of 2 - 48 hours, at its target site in the subject, being in the interval of 10-25% of the immediate peak output rate.

[0038] In some aspects, in the method above, the pharmaceutical substance, upon administration to a subject, exhibits a cumulative amount, at its target site in the subject, which is increasing but at a successively lower rate up to at least 8 hours.

[0039] In some aspects, in the method above, at least 10, 20, 30, 40, 50, 60, 70, 80 or 90% of the pharmaceutical substance released from the nasal device and delivered to the body of the subject, is delivered to the body via the nasal cavity, of which at least 30, 40, 50, 60, 70, 80 or 90 % is delivered via the olfactory bulb. Thus, by using the nasal device of the present disclosure a high amount of the pharmaceutical substance can reach the olfactory bulb and / or the trigeminal nerve of the nasal cavity and thereby be delivered essentially directly to the central nervous system.

[0040] Further, a pharmaceutical composition is provided comprising at least one pharmaceutical substance for use in administration of the substance to a target site in the body of a subject via the olfactory bulb, the trigeminal nerve, upper airways, nasal mucosa, lungs and / or a combination thereof, wherein the pharmaceutical substance is released in gaseous form from a nasal device as disclosed herein.

[0041] In some aspects, the pharmaceutical substance comprises one or more of L-Dopa, codeine, oxytocin, lorazepam, desogestrel, progesterone, rimantadine, noxytiolin, L-(-)- menthol, dexfenfluramine, anethol, pentorex, fenfluramine, fomepizole, valproic acid, memantine, nicotine, iron, vitamins such as B12, cytizine, morphine, fentanyl, triptans, various vaccines, adrenaline, amphetamine, Zyprexa (olanzapine), carbamazepine, azelastine, fluticasonpropionate, mometasone, naloxone, xylometazoline, apomorphine, or any substance effective on the central nervous system, including anesthetics, anticonvulsants, antiemetics, anti-Parkinson agents, CNS stimulants, muscle relaxants, narcotic analgesics (pain relievers), nonnarcotic analgesics (such as acetaminophen and NSAIDs), and sedatives.

[0042] In some aspects, the aim using such composition is to treat a condition, state or disease that is partially or completely curable by the administration of a therapeutically effective amount of the pharmaceutical substance. Such pharmaceutical composition may e.g., include at least one pharmaceutical substance being the active ingredient, such as salts, solvates and hydrates of a pharmaceutical substance having therapeutic activity. Further, the pharmaceutical composition may comprise additional substances for improving and / or facilitating storage, viscosity and / or other physicochemical features.

[0043] In some aspects, the pharmaceutical composition is provided so that a combinatory effect is obtained, wherein a quick effect is obtained by delivery via the olfactory bulb and / or the trigeminal nerve to the central nervous system, and a slow release effect is obtained by delivery via the upper airways, nasal mucosa and / or lungs to the blood stream and subsequently to bodily organs.

[0044] In some aspects, the pharmaceutical substance in the composition, upon administration to a subject, exhibits an immediate peak output rate, measured after about 10 minutes - 2 hours, and a slow-release output rate, measured at some point in time after a duration of 2 - 48 hours, at its target site in the subject, being in the interval of 10-25% of the immediate peak output rate. In some aspects, the pharmaceutical substance in the composition, upon administration to a subject, exhibits a cumulative amount, at its target site in the subject, which is increasing but at a successively lower rate up to at least 8 hours.

[0045] In some aspects, the pharmaceutical composition is provided so that at least 10, 20, 30, 40, 50, 60, 70, 80 or 90% of the pharmaceutical substance released from the nasal device and delivered to the body of the subject, is delivered to the body via the nasal cavity, of which at least 30, 40, 50, 60, 70, 80 or 90 % is delivered via the olfactory bulb. Thus, by using the nasal device of the present disclosure a high amount of the pharmaceutical substance can reach the olfactory bulb and / or the trigeminal nerve of the nasal cavity and thereby be delivered essentially directly to the central nervous system.

[0046] In some aspects, a kit of nasal devices is provided, comprising more than one nasal device as disclosed herein and intended for use in delivery of at least one pharmaceutical substance. Such a kit may further comprise instructions for use.

[0047] Each plug in the kit may have the same or different concentrations and / or doses of the composition comprising at least one pharmaceutical substance to be delivered to the user.

[0048] Hence, since delivery of pharmaceutical substance may advantageously comprises exposing the subject to a plurality of compositions comprising at least one pharmaceutical substance over time, it will be convenient for the subject to be provided with a set of different nasal devices, each comprising different compositions comprising at least one pharmaceutical substance and / or different concentrations of substance. Hereby, the likelihood of subject compliance and a successful delivery of pharmaceutical substance is improved. Hereby, by combining a plurality of different substances a combined effect may be obtained.

[0049] According to some aspects, the kit comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 different nasal devices with different compositions comprising at least one pharmaceutical substance and / or different doses of the same composition comprising at least one pharmaceutical substance. Thus, the content of the kit according to the present disclosure can be varied depending on the individual desired choice of pharmaceutical substance and / or dosage, and depending on the subject's need.

[0050] In other aspects, a method is provided for producing a nasal device for use in delivery of at least one pharmaceutical substance, wherein the nasal device is adapted for insertion into a nostril of a human subject. Such method comprises the steps of: a. providing and mixing (i) a material for the nasal device to be molded and a pharmaceutical composition comprising at least one pharmaceutical substance, so that the composition and the substance comprised in the composition is evenly dispersed in the structural molded material; b. using the mixture of step a. in a molding process to form nasal devices, wherein the mixture is exposed to a temperature of at least about 150°C.

[0051] In this method for producing a nasal device, the substance essentially maintains the pharmaceutical properties during the production process, and the substance is released in gaseous form by diffusion from the nasal device at a rate and duration suitable for administration via the olfactory bulb, the trigeminal nerve, upper airways, nasal mucosa and / or a combination thereof.

[0052] According to a yet another aspect, there is provided a computer program for use in delivery of pharmaceutical substance according to the aspects described above , comprising instructions which, when executed on at least one processor, cause the at least one processor to provide guidance to a subject undergoing delivery of pharmaceutical substance in accordance with methods disclosed herein, and / or following up activities performed by said subject as part of said delivery of pharmaceutical substance.

[0053] Hereby, a tool, e.g. in the form of an app (application) on a mobile device or computer or the like, that further facilitates the continuation and completion of delivery of pharmaceutical substance is provided.

[0054] Effects and features of the kits, methods and computer programs described herein are to a large extent analogous to those described above in connection with the nasal devices. Aspects mentioned in relation to the disclosed nasal devices are largely compatible with the kits and methods described herein, and vice versa.

[0055] Further, also any non-pharmaceutical additives or carrier substances may be included in the nasal device, either incorporated together with a pharmaceutical substance in the structural molded material or e.g. coated or otherwise included in the nasal device.

[0056] The terms "nose plug" and "nasal device" as used herein is meant to apply to any nasal device inserted into the nasal cavity, partly or fully, and is not meant to suggest that the device stops or hinders air flow through the nose. The terms "nose plug" and "nasal device" are used interchangeably throughout the present disclosure.

[0057] The term "structural molded material" entails that the nose plug or nasal device has a structural molded shape, e.g. a plug part, adapted for insertion into the nostril, or a holder member, adapted for arrangement in the nostril opening. In some aspects, the structural molded material forms essentially the entire nasal device; in other aspects the entire nasal device comprises the structural molded material. In some aspects, specific parts of the nasal device comprise the structural molded material with incorporated the substance or compositions, and other parts may comprise the structural molded material without the substance or compositions.

[0058] The present disclosure will become apparent from the detailed description given below. The detailed description and specific examples disclose preferred embodiments of the disclosure by way of illustration only. Those skilled in the art understand from guidance in the detailed description that changes and modifications may be made within the scope of the disclosure.

[0059] Hence, it is to be understood that the herein disclosed disclosure is not limited to the particular component parts of the device described or steps of the methods described since such device and method may vary. It is also to be understood that the terminology used herein is for purpose of describing particular embodiments only, and is not intended to be limiting. It should be noted that, as used in the specification and the appended claim, the articles "a", "an", "the", and "said" are intended to mean that there are one or more of the elements unless the context explicitly dictates otherwise. Thus, for example, reference to "a device" or "the device" may include several devices, and the like. Furthermore, the words

[0060] "comprising", "including", "containing" and similar wordings does not exclude other elements or steps.

[0061] Brief descriptions of the drawings

[0062] The above objects, as well as additional objects, features and advantages of the present disclosure, will be more fully appreciated by reference to the following illustrative and non-limiting detailed description of example embodiments of the present disclosure, when taken in conjunction with the accompanying drawings.

[0063] Figure 1 shows an aspect of a nose plug or nasal device as disclosed herein in a perspective view,

[0064] Figure 2 illustrates the nose plug in figure 1 from above,

[0065] Figure 3 illustrates a cut along A-A in figure 2,

[0066] Figure 4 illustrates a cut along B-B in figure 2,

[0067] Figure 5 shows a perspective view of a nose plug as disclosed herein moulded by using a 2K technique,

[0068] Figure 6 illustrates another aspect of a nose plug,

[0069] Figure 7 shows a helical aspect of a nose plug in a perspective view,

[0070] Figure 8 shows a helical aspect of a nose plug from above,

[0071] Figure 9a and 9b show two perspective views of another aspect of a nasal device,

[0072] Figure 10 and 10b show two perspective views of yet another aspect of a nasal device,

[0073] Figures 11a and lib show the results of Example 2 tests,

[0074] Figures 12a and 12b show the results of Example 3 tests,

[0075] Figures 13a and 13b show the results of Example 4 tests, Figures 14a and 14b show the results of Example 5 tests,

[0076] Figures 15a and 15b show the results of Example 6 tests, and

[0077] Figures 16a and 16b show the results of Example 7 tests.

[0078] Detailed description

[0079] The present disclosure will now be described with reference to the accompanying drawings, in which preferred example embodiments of the disclosure are shown. The disclosure may, however, be embodied in other forms and should not be construed as limited to the herein disclosed embodiments. The disclosed embodiments are provided to fully convey the scope of the disclosure to the skilled person.

[0080] The nasal device

[0081] The nasal device disclosed herein for use in drug delivery may be a nasal device adapted for insertion into a nostril of a human subject, wherein the nasal device comprises a structural molded material and at least one composition. The composition comprises at least one pharmaceutical substance, and optionally other components such as a solvent, auxiliary substances and / or excipients, and / or other components that are suitable and / or necessary for the composition and the substance comprised in the composition to work. Further, the composition is evenly dispersed in the structural molded material. The composition is composed to essentially maintain the pharmaceutical properties of the pharmaceutical substance during a production process for the nasal device, the process comprising a production temperature of at least about 150°C. The substance is adapted to be released in gaseous form from the nasal device at a rate and duration suitable for administration of the substance via the olfactory bulb, the trigeminal nerve, upper airways, nasal mucosa and / or a combination thereof.

[0082] Hereby, by providing a nasal device according to any aspect disclosed herein that comprises a composition comprising at least one pharmaceutical substance that is to be used in delivery of the pharmaceutical substance, a convenient device for the subject is provided, making it easy to perform a controlled delivery of a pharmaceutical substance.

[0083] Herein, the term "nose plug" is used interchangeably with the term "nasal device". As mentioned and further exemplified in the herein described aspects, neither of the terms are meant to in any way describe a device that hinders airflow in and out of the nose. In fact, the disclosed nasal devices are adapted to allow free airflow during breathing, and in some aspects, will lengthen the airflow path, to allow the air to come in contact with the composition comprising at least one pharmaceutical substance for a longer time before passing through the device. Various configurations of such a nose plugs or nasal devices are conceivable.

[0084] The term "structural molded material" entails that the nasal device has a structural molded shape, or plug part, adapted for insertion into the nostril. In some aspects, parts of the nasal device are inserted into the nasal cavity, and in other aspects, the nasal device is adapted for arrangement mainly at or within the nostril opening. Various aspects will be described in more detail below.

[0085] The structural molded material is preferably made of one of or a combination of any moldable material suitable for use in a nostril. Examples include plastic materials, various polymers or a cellulose-based material, such as silicone elastomers, thermoplastic elastomers (TPE) , thermoplastic polyurethane (TPU), polyethylene (PE), polyethylene terephthalate (PET), polyvinylchloride (PVC), polyurethanes (PUR), fluoropolymers (PTFE, FEP, PFA, EFTE, ECTFE, PVDF), polyamide (PA), polypropylene (PP), polystyrene (PS), polylactic acid (PLA), polycarbonate (PC), polyetheretherketone (PEEK), polyactide (PLA) plastic, or polyhydroxyalkanoate (PHA) plastic, molded paper pulp, or molded cellulose fiber pulp. In a preferred aspect, the structural molded material comprises mainly thermoplastic elastomers (TPE).

[0086] In other aspects, a method is provided for producing a nasal device for use in delivery of at least one pharmaceutical substance, wherein the nasal device is adapted for insertion into a nostril of a human subject. Such method comprises the steps of: c. providing and mixing (i) a material for the nasal device to be molded and a pharmaceutical composition comprising at least one pharmaceutical substance, so that the composition and the substance comprised in the composition is evenly dispersed in the structural molded material; d. using the mixture of step a. in a molding process to form nasal devices, wherein the mixture is exposed to a temperature of at least about 150°C.

[0087] In this method for producing a nasal device, the substance essentially maintains the pharmaceutical properties during the production process, and the substance is released in gaseous form by diffusion from the nasal device at a rate and duration suitable for administration via the olfactory bulb, the trigeminal nerve, upper airways, nasal mucosa and / or a combination thereof.

[0088] In some aspects, the nasal device is molded in one piece, such that the entire nasal device comprises the composition comprising at least one pharmaceutical substance evenly dispersed in a structural molded material. This is advantageous as manufacturing is simplified, in having only one molding step. All-in-one molding may also decrease the risk of any structural integrity flaws in the device.

[0089] One aspect of this disclosure, illustrated in Figures 1 to 8, shows a nose plug or nasal device for use in delivery of pharmaceutical substances, comprising:

[0090] - at least one flexible member 2 and

[0091] - one rigid, elongated support member 3,

[0092] - wherein the flexible member is arranged to surround the support member, and

[0093] - the flexible member is adapted to be placed within a nostril to accurately fill the opening of the nostril, and is provided with means for guiding the flow of air entering the nostril in a serpentine or spiral like path by means of a plurality of plates or a band, characterized in that the flexible member comprises at least one composition comprising at least one pharmaceutical substance. In this aspect, the flexible member comprises the plug part of the nasal device.

[0094] The expression "nose plug" used in this application is not a stopper in the sense to close the nostrils completely. While a flexible member fills the nostril, thereby hindering air from flowing straight into the nose, it is not intended to hinder air from entering. In fact, the disclosed nose plug may for many users actually enhance ease of flow of air in and out of the nose, as the configuration of the flexible members may widen the nostril slightly and / or support a more open shape of the nostril when placed in the nostril. Through enabling air to flow in a tortuous structure, thus over a longer distance than without the nose plug, and the air thus being exposed to a larger surface area of the structural molded material along the path through the nasal device, results in an increased release of the substance from the structural material into the air flow. Thus, an improved efficiency of delivery of the substance into the inhaled air is achieved, and therefore also a more concentrated dose is delivered to the user. Thus, the combination of the longer air path and the increased surface area of the structural molded material, and the manner in which the substance is initially incorporated into the nasal device results in an overall highly improved delivery compared to other drug delivery methods.

[0095] In another aspect, illustrated in Figures 9a, 9b, 10a and 10b, a nasal device may comprise an elongated support member 12, 62, and one or two rounded holder members 13, 63, each arranged at a respective end of said elongated support member 12, 62, wherein said holder members 13, 63 are adapted to be inserted into the nostril with a distal end directed into the nostril, and a proximal end adjacent the nostril openings, said holder members 13, 63 each comprise a bell-shaped cross-section in at least one plane in a distal-proximal extension, said holder members 13, 63 each comprising a rounded distal portion 15, and an open proximal portion 17, 67 comprising an outer rim 18, 68 disposed circumferentially around the outer perimeter of said proximal portion 17, 67 and extending radially outward from said holder member 13, 63, and an intermediate waist portion 19, 69 arranged between said distal portion 15 and said proximal portion 17, 67, said intermediate portion 19 having at least one outer circumference in a plane essentially transverse to a distal-proximal direction, said outer circumference being smaller than a respective largest outer circumference of at least said distal portion 15, wherein said outer rim 18, 68 disposed circumferentially around the outer perimeter of the proximal portion 17, 67 is adapted to engage with the nostril opening and protrude outward from the nostril when the nasal device is arranged in a nostril, wherein said rounded distal portion 15 is provided with one or more through-going holes (6, 66) adapted to allow air to pass through said distal portion 15, wherein at least holder members 13, 63 comprise the at least one composition comprising at least one pharmaceutical substance evenly dispersed in a structural molded material. In this aspect, the holder membersl3, 63 comprise the plug part of the nasal device.

[0096] The shape of the holder members 13, 63 comprising an intermediate waist portion allows the holder member to securely fit in the nostril opening, thus allows for a comfortable and discrete fit. The nasal devices of figures 9a, 9b, 10a and 10b also provide for a large surface area, such that air inhaled by the user is effectively saturated with released substance from the structural molded material.

[0097] In some aspects, not illustrated, a nasal device such as that shown in Figures 9a and 9b, or 10a and 10b, may be provided with an attached and / or integrated filter member. Such filter member may be provided only for particle filtration, or also saturated with a suitable further substance for delivery to the user.

[0098] One material suitable for forming the nasal devices herein, i.e. at least a flexible or holder member and optionally as a support member in the nasal device according to the present disclosure, may be prepared by mixing the composition comprising at least one pharmaceutical substance and thermoplastic elastomer to provide a thermoplastic elastomer containing the desired amount of substance. For example, a nasal device may be provided comprising a specific total amount of substance, the exact amount depending on the type of substance. In some aspects, the structural molded material may be made of a thermoplastic elastomer and the composition comprising at least one pharmaceutical substance, wherein the substance or composition typically constitutes a percentage in the range of 1 and 20% of the total material in the structural molded material, or more preferably in the range of 3% to 10%. In some aspects, the substance constitutes approximately 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% of the material in the structural molded material.

[0099] In some aspects, the entire nasal device comprises the composition comprising at least one pharmaceutical substance evenly dispersed in a structural molded material.

[0100] In some aspects, the structural molded material may be made of a thermoplastic elastomer and the composition comprising at least one pharmaceutical substance evenly dispersed in the structural molded material, wherein the substance or compositions constitutes a specified amount per nasal device. This amount depends on the choice of substance or compositions. Several examples are illustrated in the Examples herein.

[0101] The composition comprising at least one pharmaceutical substance is incorporated or added to the structural molded material of nasal device in such way that as slow-release effect is achieved, i.e. so that the release of the substance is distributed over time for a prolonged life time of the nasal device, and / or for an increasing or decreasing release over time, to suit the intended effect.

[0102] Figure 1 shows a nose plug 1 comprising a set of flexible members 2 comprising a composition comprising at least one pharmaceutical substance and one rigid, elongated support member 3 adapted to stabilize the flexible member. In this aspect of the nose plug the set of flexible members 2 comprise parallel plates 4 surrounding the support member. Between adjacent plates there are spaces 5. Furthermore, there is provided for communication between these spaces through the plates. When the nose plug is placed in a nose and the flexible plates accurately fill the openings of the nostrils, air entering the nostrils will, when passing through the nose plug, first enter through a recess 7 in a first lowermost plate. The air flow then passes the nose plug in a tortuous manner and exits through a recess 6 in an uppermost final plate. Exhaled air will flow in the opposite direction. Thus, both when air is inhaled and when air is exhaled, the air will flow over a longer distance than without the nose plug arranged in the nostril and will be exposed to the composition in both directions.

[0103] Throughout the passage through the nose plug, the air is in contact with the flexible member comprising a substance. This aspect illustrates a much extended path for the air to flow through, since every second recess is on a position at the periphery that is opposite on the transverse diameter in relation to the recess on an adjacent plate. The recess 7 of the first plate and the recess 6 of the final plate and all the recesses there between are clearly seen in figure 4, i.e. the recess 7 of the first lowermost plate and the recess of every second plate counted from the first plate has the same reference number and the recess 6 of the uppermost final plate and every second plate counted from the final plate has the same reference number. This is valid when the number of plates is an even number (as shown in the aspects in figure 1 to 6), otherwise in the case where the number of the plates is uneven the recess of the first and the final plate will have the same reference number.

[0104] In the aspects of a nose plug seen in figure 1 to 6 the set of flexible members 2 comprising a substance is adapted to guide the flow of air entering the nostril in a serpentine or meandering like path. This is achieved when the nose plug is placed in a nostril. The air flow enters the nose plug 1 through the recess 7 of the lowermost plate 4, the air flow is then passing in the space 5 between two adjacent plates, i.e. the first and second plate, arriving at the opposite transverse diametrical end of the first plate, where the air flow is further guided through the recess 6 of the second plate. Thereafter the air flow is passing between two further adjacent plates, i.e. the second and third plate, arriving at the opposite transverse diametrical end of the second plate, where the air flow is further guided through the recess 7 of the third plate. And so on, until the air flow passes between the two uppermost plates and exits into the nostril through the recess 6 of the final plate.

[0105] In the aspect illustrated in figure 1 to 4 the number of the plates is 6 and in figure 5 and 6 the number of the plates is 8. The number of the plates may also be another number such as 7, 9 or 10. The number of the plates is preferably ranging from 4 to 12.

[0106] Figure 2 shows the nose plug of the aspect in figure 1 from above. As may be seen the plates 4 have an elliptical shape. The final uppermost plate is the smallest (transverse diameter and conjugate diameter) and the plates in the middle, i.e. plate number four and / or five is / are the largest plate(s). The first plate is somewhat larger than the final plate. Seen from the first plate each further adjacent plate has somewhat larger diameters, until the fourth or fifth plate, thereafter each further adjacent plate has somewhat smaller diameters, i.e. from the first to the fourth or fifth plate the transverse and conjugate diameter increases for each plate, from the fourth or fifth plate to the final plate the transverse and conjugate diameter diminishes for each plate. The increase or the diminution of each adjacent plate may be linear, but may also progress irregularly.

[0107] In figure 2 are the lines A-A and B-B shown. The line A-A coincides with the conjugate diameter of the plates and line B-B coincides with the transverse diameter of the plates.

[0108] The flexible members 2 comprise a composition comprising at least one pharmaceutical substance. The composition can be incorporated within the material constituting the flexible member 2, such as evenly dispersed within the material.

[0109] The flexible member 2 is preferably made of a thermoplastic elastomer, or other suitable polymer, with a composition comprising at least one pharmaceutical substance dispersed evenly throughout the thermoplastic elastomer using any suitable manufacturing technique. In one aspect, the composition may be introduced into the thermoplastic elastomer or other suitable flexible material by using an additive master batch approach. In addition or as an alternative, a composition may be introduced by coating the flexible member and in some aspects, also the support member, with a composition in a suitable solution or dispersed into a thermoplastic elastomer or other suitable material. Thus, the flexible member 2 may be made of a thermoplastic elastomer with a composition comprising at least one pharmaceutical substance coated on the surface.

[0110] Other flexible materials may also be used in the flexible member and / or support member. The support member is preferably made of a thermoplastic polymer. Other firm or rigid materials are also possible to use. In some aspects, the support member and / or the flexible member may further comprise one or several reinforcing members, such as an internal core of a more rigid and / or shapeable material, such that parts of the nose plug may be more inflexible and / or the support member may be pressed into a shape to better fit an individual nose or nostril.

[0111] In figure 3 a cross-sectional view along A-A be seen. In this figure a set of flexible members 2 are integrally formed with the respective ends of support member 3, and the flexible members 2 surround the ends of support member 3. The support member 3 has a generally U-shaped form and has two sets of flexible members 2 attached thereto, one set on each end. The support member 3 extending between the two ends has a bent shape, in order to be easy to handle.

[0112] In figure 4 a cross-sectional view along B-B shown. This cut coincides with the transverse diameters of the plates 4. Therefore, the recesses 6 of every second plate are shown on the one side and the recesses 7 of every other second plate are shown on the other side.

[0113] As can be seen in figure 5 the two legs of the generally U-shaped support member 3 may be slightly inclined and / or angled in relation to each other. This facilitates adapting the nose plug to the extension and arrangement of the nostrils. The plug should be properly arranged within the nose, without widening the nostrils more than necessary.

[0114] The nasal device according to the present disclosure may be manufactured by moulding using a 2K technique, where two materials are moulded together. Thus, it is possible to first mould the support member in one material, and thereafter mould the flexible members directly onto the support member, using the same or different materials. This is illustrated in figures 5 to 7. The same applies to the nasal device described in connection with Figures 9a, 9b, 10a and 10b below. The method of manufacturing the nasal device may also comprise other techniques, such as extrusion moulding, injection moulding, casting, compression moulding, transfer moulding or any other suitable technique for the material used. In some aspects, only one material may be used for manufacturing the entire nasal device, i.e. the same material for the flexible member or the holder member as for the support member. The composition will then be dispersed throughout the entire nasal device. Furthermore, the flexible member or holder member and the support member comprised in the nasal device according to the present disclosure may also be manufactured by moulding them separately, using the same material or two different materials, and thereafter assembling the two parts together. In such cases, the content of the substance can be adapted to different parts of the nasal device.

[0115] The present disclosure supports the conclusion that the combination of the air being led through a longer path and / or being exposed to a larger surface area of the structural molded material, without causing inhibition of air flow, and an incorporated substance in the material of the nasal device and thus along all surfaces of such a path, result in a very effective, comfortable and easy to use nasal device for improving the delivery of pharmaceutical substances to a subject. More specifically, as mentioned previously, in some aspects, the arrangement of the flexible member of the nose plug allows air to be led through a longer path than in a nostril without a nose plug, while maintaining ease of breathing for a user. When the arrangement of the flexible members is combined with a substance being incorporated in the material, a significant effect of delivery is achieved.

[0116] Figure 6 illustrates an aspect, wherein each nose plug 1, comprising one flexible member 2 arranged on a support member 3, is adapted to be arranged separately in one nostril each.

[0117] Figure 7 shows an aspect with a flexible member 2 comprising a helically arranged band in a perspective view. This spiral-like structure gives the air entering the nostrils an extended path. The distance of the path may be varied due to the pitch angle of the helical wings of the band. There may also be recesses provided on the helically arranged band. However, since air is allowed to enter without recesses, this is not an essential feature.

[0118] In figure 8 the aspect in figure 7 is seen from above. The helically arranged band shown in figure 7 and 8 shows the flexible member 2 being adapted to guide the flow of air entering the nostril in a spiral like path.

[0119] Figures 9a and 9b show different perspective views of a further aspect of a nasal device 10, and figures 10a and 10b show different perspective views of another aspect of a nasal device 61. Regarding the structural molded material, the at least one substance or mixture of substances evenly dispersed in a structural molded material and the possible manufacturing techniques; these aspects may all be as described for aspects described above.

[0120] The nasal devices 10, 61 of figures 9a, 9b, 10a and 10b comprise a semi-rigid, elongated support member 12, 62. At both ends of the support member 12, 62, two rounded holder members 13, 63 are provided, wherein the distal end 14, 64 of each of the rounded holder members are adapted to be inserted distally into a respective nostril. The shape of the holder members provide an intermediate waist portion 19, 69, adapted to "hang" in the nostril opening, with the wider distal portion 15 and wider proximal portion 17, 67 providing a secure fitting in the nostril opening. The outer rim 18, 68 is disposed circumferentially around the outer perimeter of the proximal portion 17, 67 and is adapted to engage with the nostril opening and protrude outward from the nostril when the nasal device is arranged in a nostril.

[0121] The rounded distal portion 15 is provided with one or more through-going holes 16, 66 adapted to allow air to pass through the holder members 13, 63. In these aspects of nasal devices, at least the holder members 13, 63 comprise the at least one substance or mixture of substances evenly dispersed in a structural molded material.

[0122] Similar to previous aspects, the combination of large surface area allowing release of the substance into the air flow being inhaled by the user, and the manner in which the substance has been incorporated into the structural molded material, provides an effective delivery of the substance to the user.

[0123] Further, the above mentioned and described aspects and embodiments are only given as examples and should not be limited to the present invention. Other solutions, uses, objectives, and functions within the scope of the invention as claimed in the accompanying patent claims should be apparent for the person skilled in the art.

[0124] Pharmaceutical substances

[0125] As detailed above, a nasal device comprising at least one composition, wherein the composition comprising at least one pharmaceutical substance, may be used for efficient drug delivery via the nasal cavities. Such nasal devices and methods described herein are especially suitable for delivery to the central nervous system, including the brain. As discussed above, various aspects of such substances contribute to achieving the advantages presented herein.

[0126] The following substances (Table 1) are examples of substances that would be suitable for use in the nasal device of the present disclosure, either as an essentially sole component of a compositions to be included in the nasal device material, or to be included with a solvent, auxiliary substances and / or other components in a composition to be used in the nasal device.

[0127] Table 1.

[0128] According to some aspects, the composition comprising at least one pharmaceutical substance is chosen from the group of compositions that are suitable to be administered intra- nasally and / or via the nasal device according to this disclosure, e.g. those according to Table 1. This may e.g. include pharmaceutical substances or compositions of small molecule types, larger and more complex molecule types, as well as peptides, RNA molecules and vaccines. Also, substances that have properties facilitating uptake to the central nervous system, i.e., by-passing the blood brain barrier by the intra-nasal route, may be used in certain aspects. This could e.g. include small molecule-based substances or compositions.

[0129] In one aspect, the composition comprising at least one pharmaceutical substance evenly dispersed in a structural molded material is nicotine. Such a nasal device is useful for the treatment of nicotine addiction. An advantage of a nasal device as disclosed herein comprising nicotine, is the combination of a quick effect after applying the nasal device, and a long-lasting effect over time. Known administration methods, will often only provide either a quick effect, such as for chewing gum or pills, or a long-lasting effect, such as for an adhesive plaster, but not a combined effect. Further, because nicotine acts directly on the central nervous system, the nasal delivery device and methods disclosed herein are especially advantageous, as nicotine may be delivered directly to the central nervous system via the olfactory bulb and the trigeminal nerve, in combination with via the airways and lungs. Thus, a quicker and more effective delivery is achieved, e.g. delivering an initial peak amount quickly, and thereafter a slow release of a lower dose over a longer time period, such as up to at least 8 hours, or up to 24 hours. Further, by not having a major amount of nicotine pass through the liver, a smaller amount is lost, thus needing a less amount of nicotine in the nasal device to achieve a similar effect as a larger amount administered through the known routes via pills, plasters or sprays. Examples 1 through 4 below illustrate how a nasal device comprising nicotine is manufactured and further the release and delivery of nicotine to the relevant parts of the nasal cavity.

[0130] In another aspect, the composition comprising at least one pharmaceutical substance evenly dispersed in a structural molded material is a triptan. Such a nasal device is useful for the treatment of migraines. Also here, the combination of a quick first effect and a long-lasting effect is advantageous.

[0131] In another aspect, the composition comprising at least one pharmaceutical substance evenly dispersed in a structural molded material is 4-methylpyrozole (fomepizole). Such a nasal device is useful for the treatment of methanol or ethylene glycol poisoning, as 4- methylpyrozole is an inhibitor of alcohol dehydrogenase and is used as an antidote. Traditionally, 4-methylpyrozole is administered intravenously over a longer period of time. Using a nasal device according to the present disclosure provides an easy and effective way of delivery over a longer period of time. Further, as the method is noninvasive, it is more comfortable and less risky for the patient.

[0132] In another aspect, the composition comprising at least one pharmaceutical substance evenly dispersed in a structural molded material is memantine. Memantine is used for treatment of Alzheimer's disease, and common side effects include constipation and increased liver markers when administered through the traditional route of oral administration. Using the herein disclosed nasal device and methods lessens the pressure on the liver and digestive system, thus providing a more efficient delivery and decreases the side effects. Further, a smaller dose via the herein disclosed device and administration will provide the same effect as a larger dose administered via the digestive route.

[0133] In another aspect, the composition comprising at least one pharmaceutical substance evenly dispersed in a structural molded material is valproic acid. Valproic acid is used for treatment of e.g. epilepsy, a disease of the central nervous system. Thus, administration via a more direct route as disclosed herein provides a quicker and more efficient delivery, and similar to the above substances, lessens the load on the liver, compared to the traditional oral or intravenous administration.

[0134] As mentioned, Example 1 below shows an example of how a nasal device according to the present disclosure may be manufactured. Examples 2 to 7 below illustrate the highly efficient release and delivery of different pharmaceutical substances to a user from such a nasal device. For instance, it is clear from Example 2 that nasal devices where the incorporated substance, nicotine in this case, is provided in its liquid (oil-like) form results in an effective release over time in liquid, mimicking the contact with wet nasal membranes. On the other hand, nasal devices with nicotine in powder form (as a salt) do not allow any significant release at all. As seen in both liquid, air and nasal cast tests, when using the nasal device with nicotine in its oillike form, there is a quick release effect once initiated, as well as a long-lasting release over the 8 hours tested. This is illustrated in Examples 2, 3 and 4, and Figures 11a to 13b. Similar release curves are applicable to three other pharmaceutical substances, as shown in Examples 5 to 7. This indicates that the nasal devices disclosed herein provide both a quick effect, once applied to a nasal cavity, as well as a long-lasting effect over at least 8 hours time, and up to 24 hours. Further, the three different doses tested in Example 4 indicate that the total dosage per administered nasal device can be varied with resulting similarly shaped delivery curves over time. This indicates that the dose may be varied according to e.g. a patient's needs.

[0135] The Examples disclosed herein illustrate that the described nasal device and related methods herein are applicable to delivery of at least nicotine, 4-methylpyrozole (fomepizole), memantine and valproic acid. The different pharmaceutical substances show similar and consistent results, and thus show that the present nasal device and delivery method is highly applicable to other pharmaceutical substances. All four tested substances show a similar release pattern over time. The substance is released over a time period of at least 8-24 hours. An initial peak amount is released within 30-60 minutes, and thereafter the substance is released in lower amounts but over a time period of at least up to 8 hours. The combined effect of an initial quick peak amount followed by a slower release over a longer time period is useful for delivery of many types of pharmaceutical substances and treatment situations.

[0136] Further, the test setup using a nasal cast, as shown in Examples 4 to 7, indicates that a high percentage (at least 30 to 60%, in some instances over 75 %) of the delivered amount of substance from the nasal device appears to stay in the nasal tract, and especially in the middle part of the nasal tract, which collects at least 50%, in some instances over 70 %, of the total nasal amount. This shows that delivery using the nasal device of the present disclosure enables the pharmaceutical substance to be easily absorbed and distributed directly to the central nervous system, which is primarily obtained by distribution via the olfactory bulb and / or the trigeminal nerve. Other delivery methods, such as nasal spray, dry powders or inhalers, mainly end up in the airways and lungs, and are absorbed through the various membranes. Such delivery routes are to a large extent hindered to access the central nervous system by the blood-brain barrier.

[0137] Providing the composition comprising at least one pharmaceutical substance evenly dispersed in the structural molded material provides a nasal device that when removed from a protective packaging and placed in a user's nostrils will release the substance directly into the air surrounding the structural molded material, and making it readily available to all parts of the nasal cavity, including the olfactory bulb and nasal membranes.

[0138] A plurality of compositions comprising at least one pharmaceutical substance can be used for simultaneous, overlapping or sequential delivery, as long as the compositions can be incorporated in the structural molded material of the nasal device, and the composition is suitable for nasal delivery.

[0139] According to some aspects, the at least one composition comprising at least one pharmaceutical substance is added to the structural molded material at a dosing concentration in a range of specific intervals.

[0140] Thus, the amount and / or concentration of added composition comprising at least one pharmaceutical substance is important to accomplish that the nasal device can be used over a longer time-period, and so that the composition comprising at least one pharmaceutical substance is administered to the user at a specific level. The actual concentration of a substance may vary depending on the composition comprising at least one pharmaceutical substance and the desired effect.

[0141] According to some aspects, the structural molded material is made of a thermoplastic elastomer and the composition comprising at least one pharmaceutical substance is evenly dispersed therein.

[0142] The kit of nasal devices

[0143] Another aspect of this disclosure shows a kit of nasal devices for delivery of pharmaceutical substances, wherein each nasal device is as defined in any of the above described aspects, each nasal device comprising one composition comprising at least one pharmaceutical substance, the kit further comprising:

[0144] - nasal devices for one composition comprising at least one pharmaceutical substance or a plurality of different compositions and / or dosages of a substance or mixtures of substances, and - instructions for use.

[0145] It is intended that the kit of nasal devices comprises a plurality of nasal devices, wherein each nasal device comprises one composition comprising at least one pharmaceutical substance, so that the kit comprises the necessary compositions or mixture of compositions to perform controlled delivery of pharmaceutical substances. Such delivery of pharmaceutical substances may differ between subjects, and according to the subject's needs.

[0146] In some aspects, the kit comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 or even more different nasal devices with different substances or mixtures of substances.

[0147] Also, since it may be beneficial to provide nasal devices having different concentration and / or amount of substance depending on need of the subject, the kit could comprise nasal devices having different concentrations and / or amounts, such as low, medium and / or high concentration / amount.

[0148] According to some aspects, the kit comprises nasal devices for about 10 to 100 different dosages of a particular composition comprising at least one pharmaceutical substance.

[0149] According to some aspects, the kit comprises a plurality of nasal devices for each dosage of a particular composition comprising at least one pharmaceutical substance.

[0150] Since the effect of the composition comprising at least one pharmaceutical substance associated with the nasal device may decrease over time, and / or the nasal device itself may become broken or dirty, a kit comprising a plurality of nasal devices having the same composition comprising at least one pharmaceutical substance can be advantageous in some cases. For example, the kit may comprise 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 nasal devices for each composition comprising at least one pharmaceutical substance. However, the nasal devices as described herein are adapted to be used at least up to 8 hours a day, if needed. In some aspects, the nasal devices as described herein are adapted to be used at least up to 12, 24 or 48 hours continually or with specified periods of pausing the delivery by removing the nasal device from the nostril. Related methods

[0151] According to yet another aspect there is provided a method of treatment of a condition, state or disease that is curable partially or completely by administering a therapeutically effective amount of a suitable composition comprising at least one pharmaceutical substance using the nasal device of the present disclosure. Hereby, a quick and / or long-lasting effect of the composition comprising at least one pharmaceutical substance can be achieved. For example, such method of treatment can be used for treating a disorder, disease and / or addiction, including nicotine addiction, migraine and opioid addiction. Other examples of potential areas are various diseases affecting the central nervous system, such as multiple sclerosis, Alzheimer's disease, Parkinson's disease and various forms of cancer.

[0152] According to yet another aspect there is provided a method for delivery of a pharmaceutical substance, comprising providing a subject with a plurality of nasal devices as defined in the aspects disclosed herein, or with a kit of nasal devices as defined in the aspects disclosed herein, wherein the method comprises the steps of: a. exposing the nostril of a subject to the plurality of nasal devices comprising a set of compositions comprising at least one pharmaceutical substance in a predetermined order and duration; b. optionally repeating the exposure on a daily basis for a predetermined delivery period.

[0153] Hereby, a delivery of pharmaceutical substance taking advantage of the nasal devices comprising substance(s) is provided, thereby facilitating delivery of pharmaceutical substance for subjects and patients having various pharmaceutical needs.

[0154] According to some aspects, exposing the nostril comprises inserting a large part of the nasal device, e.g. at least an entire flexible member fully into the nostril, such that only the support member remains outside the nostril. Hereby, a strong and / or optimized effect of the substance is expected. Another advantage of fully or almost fully inserting at least the flexible member or large part of a holder member, into the nostril, is that only a small part of the nasal device protrudes from the nostril, presenting a discrete visual experience such that the user may go about their daily tasks without a bulky device visible or in the way. Notably, all aspects of nasal devices described herein offer discrete use.

[0155] According to some aspects, a nasal device used in a delivery of pharmaceutical substance as described, when comprising two parts intended for a separate nostril, may comprise different substances on each side, such that each nostril is exposed to a different composition comprising at least one pharmaceutical substance.

[0156] Hereby, by varying the delivery program in a structured way on an hourly or daily basis, improved results can often be expected.

[0157] Hereby, a structured program for delivery of pharmaceutical substance organized to help motivate and prolong efficiency is provided, for the benefit of the subject in need thereof.

[0158] Hereby, the delivery of pharmaceutical substances is intended for medical conditions as well as non-medical conditions, for subjects and patients with different needs.

[0159] Thus, these are examples of medical conditions, for which the delivery of pharmaceutical substance of this disclosure is useful in case of varying pharmaceutical needs.

[0160] The app for assisting delivery of pharmaceutical substances

[0161] According to yet another aspect, there is provided a computer program for delivery of pharmaceutical substances according to the present disclosure, comprising instructions which, when executed on at least one processor, cause the at least one processor to provide guidance to a subject undergoing drug delivery, and / or following up activities performed by said subject associated with said drug delivery.

[0162] Such computer program, which can be implemented in the form of a mobile "app" or on a computer or any other user-friendly digital device, will assist the subject in following the delivery of pharmaceutical substances in a routinely and structured manner. For example, the "app" could include reminders related to timing, duration, choice of nasal device to the subject, to facilitate the continuation and completion of the delivery of pharmaceutical substances.

[0163] Example 1 - Manufacturing of a nasal device comprising a pharmaceutical substance

[0164] Nasal devices A ("oil plugs") with three different dosages of nicotine and configured according to e.g. Figure 1 to 4 were made by initially mixing nicotine in its oil-like form ("PureNic 99+", CAS:54-ll-5 (from CHEMNOVATIC Sp. z o.o. Sp. K., Poland)) with a thermoplastic elastomer to obtain three different nasal device comprising a total amount of nicotine of 0,38 mg, 10 mg and 20 mg, respectively.

[0165] A nasal device B ("powder plug") configured according to e.g. Figure 1 to 4 was made by combining nicotine in dry powder (salt) form ("NicSalt-T", nicotine tartrate dehydrate, CAS : 6019-06-3 (from CHEMNOVATIC Sp. z o.o. Sp. K., Poland)) with a thermoplastic elastomer to obtain a nasal device comprising a total amount of nicotine of 0,38 mg.

[0166] Subsequently, each of the nasal devices A or B were molded into the shape of e.g. Figure 1 using a dedicated molding tool. Thus, nasal devices with either 0,38 mg nicotine per device, 10 mg nicotine per device, or 20 mg nicotine per device were manufactured for the for use in Examples 2 and 3. A similar procedure was used to manufacture nasal devices for use in Examples 4 to 7 by mixing a composition comprising the respective substance, or the respective substance itself with a thermoplastic elastomer, and subsequently molding into the shape of e.g. Figure 1 using a dedicated molding tool.

[0167] Example 2 - testing release of nicotine from a nasal device comprising nicotine into liquid

[0168] To evaluate the amount of nicotine released from nasal devices of each type (oil-plugs vs. powder-plugs) specified in Example 1, quantification was performed using HPLC according to known techniques (reversed phase, column: Supelcosil LC18 25 cm*4.6 mm, 5pm. Mobile phase: water-methanol-0.1 M ammonium acetate buffer (pH = 4.5)-acetonitrile - acetic acid (74 : 3 : 20 : 2 : 1 v / v), pH=4.2, Pump flow 2 mL / min, Injection volume 50pL).

[0169] For sampling in liquid a buffer solution was used (Ammonium acetate buffer 0.1M).

[0170] Tests in liquid were performed by immersing the nasal devices in 10 mL 0.1% SDS in test tubes. 0.5 mL sample solution was collected at each time point.

[0171] The results of Example 2 tests are shown in Figures 11a and lib. Figure 11a shows nicotine output rate in liquid per sample (mean n=3 samples). Figure lib shows nicotine accumulated output in liquid per sample (mean n=3 samples). These results show that in liquid, nasal devices B, i.e. using powdered nicotine, barely releases any nicotine at all. However, for the oil based nasal devices A the curve shows an increase during the first hour and then a slower release up to the 8 hours tested.

[0172] Example 3 - testing release of nicotine from a nasal device comprising nicotine into air

[0173] To evaluate the amount of nicotine released from nasal devices of each type specified in Example 1, quantification was performed using HPLC according to known techniques (reversed phase, column: Supelcosil LC18 25 cm*4.6 mm, 5pm. Mobile phase: water- methanol-0.1 M ammonium acetate buffer (pH = 4.5)-acetonitrile - acetic acid (74 : 3 : 20 : 2 : 1 v / v), pH=4.2, Pump flow 2 mL / min, Injection volume 50pL).

[0174] For sampling in air flow, 0.05M Sulphuric acid and bacterial filters were used (Respirgard II, model 303). Only nasal devices A, i.e. "oil plugs" were tested in this Example.

[0175] Tests in air flow were performed by arranging the nasal device in a closed sample chamber, and providing 7.5 L / min continuous flow through the samples. 0.05M Sulphuric acid was provided in a glass cylinder (bubble flask), and the nicotine collected using three sequentially arranged filters as specified.

[0176] The results of Example 3 tests are shown in Figures 12a and 12b. Figure 12a shows nicotine output rate in air per sample (mean n=10 samples). Figure 12b shows nicotine accumulated output in air per sample (mean n=10 samples). These results show that in air flow, the oil plugs, nasal devices A, show an increase during the first hour and then a slower release lasting at least up to the 4 hours tested.

[0177] Example 4 - testing release of nicotine from a nasal device comprising nicotine into a nasal cast

[0178] To evaluate the amount of nicotine released from nasal devices of each type of nasal device A specified in Example 1, quantification was performed using HPLC according to known techniques (reversed phase, column: Supelcosil LC18 25 cm*4.6 mm, 5pm. Mobile phase: water-methanol-0.1 M ammonium acetate buffer (pH = 4.5)-acetonitrile - acetic acid (74 : 3 : 20 : 2 : 1 v / v), pH=4.2, Pump flow 2 mL / min, Injection volume 50pL). Nasal devices A, i.e. "oil plugs" were tested, with three different doses of nicotine: 0,38 mg, 10 mg and 20 mg.

[0179] A nasal cast divided into three different parts was used to mimic the nasal cavity. The inside of the nasal cast was coated with a gel comprising Brij / glycerol solution+ 0.05M Sulphuric acid, to mimic the nasal cavity membranes. Tests using the nasal cast were performed by arranging the nasal device to be tested in the cast in a closed air flow path. To also collect any nicotine able to pass through the nasal cast, three sequentially arranged filters (Bacterial filters were coated with 0.2M oxalic acid) similar to those used in Example 3 were arranged in the air flow following the nasal cast. 7.5 L / min continuous flow was used. Quantification of the amount of nicotine was performed in the nasal cast gel and in the following filters. The nicotine amounts in the nasal cast parts and in the three filters were dissolved at specified time intervals. The time intervals used were every 30min up to 4h after that every 60min. Two runs per sample strength were performed.

[0180] The results of Example 4 tests are shown in Figures 13a and 13b. Figure 13a shows nicotine output rate in the nasal cast setup per sample (mean n=2 samples) for the three different doses using the nasal cast setup described above. Figure 13b shows nicotine accumulated output in air per sample (mean n=2 samples) for the three different doses using the nasal cast setup described above. The tests in the nasal cast show that the oil plugs, nasal devices A, show an increase during the first hour and then a slower release up to the 8 hours tested. As illustrated in Figure 13b, over the 8 hours tested, the total amount released from the 20 mg nasal device was 8000 ng nicotine. The total amount released from the 10 mg nasal device was 4000 ng nicotine. The total amount released from the 0.38 mg nasal device was 60 Hg nicotine. Half of this amount is delivered at around 3 hours. The output rate, as seen in Figure 13a, shows the highest value at the first sampling point (30 minutes).

[0181] As mentioned, the nasal cast used is divided into three nose parts ("Nose-front", "Nose-mid" and "Nose-end"), corresponding to the front- mid-, and back section of the nasal cavity, followed by three sequential filters, to catch any remaining substance in the flowing air. The filters correspond to the airways behind the nasal cavity and into the lungs. Table 2 shows the mean distribution of captured nicotine in the different parts of the setup (% of total amount).

[0182] Table 2

[0183] As seen in Table 2, about 30% stays in the nasal cast and 50% in the first filter after the nasal cast. The middle part of the nasal tract collects about half of the total nasal amount.

[0184] Example 5 - testing release of 4-methylpyrozole (Fomepizole) from a nasal device comprising 4-methylpyrozole into a nasal cast

[0185] Fomepizole is an inhibitor of alcohol dehydrogenase used as an antidote in confirmed or suspected methanol or ethylene glycol poisoning.

[0186] To evaluate the amount of 4-methylpyrozole released from nasal devices comprising 4- methylpyrozole, quantification was performed using HPLC according to the method described in Example 4. Nasal devices comprising 4-methylpyrozole in two different strengths were used, 1 mg and 20 mg 4-methylpyrozole per device. The nasal devices were manufactured essentially according to the nasal device A in Example 1, except that 4-methylpyrozole was used instead of nicotine. As in previous examples, a nasal cast divided into three different parts was used to mimic the nasal cavity. The inside of the nasal cast was coated with a gel comprising Brij / glyce rol solution+ 0.05M Sulphuric acid, to mimic the nasal cavity membranes. Tests using the nasal cast were performed by arranging the nasal device to be tested in the cast in a closed air flow path. To also collect any tested substance able to pass through the nasal cast, three sequentially arranged filters (Bacterial filters were coated with 0.2M oxalic acid) similar to those used in Example 3 were arranged in the air flow following the nasal cast. 7.5 L / min continuous flow was used. Quantification of the amount of tested substance was performed in the nasal cast gel and in the following filters. The amounts of tested substance in the nasal cast parts and in the three filters were dissolved at specified time intervals. The time intervals used were every 30min up to 4h after that every 60 min up to 8 hours and a final test at 24 hours. Two runs per sample strength were performed.

[0187] The results of Example 5 tests are shown in Figures 14a and 14b. Figure 14a shows output rate in the nasal cast setup per sample (mean n=2 samples) for the two different doses using the nasal cast setup described above. Figure 14b shows accumulated output in air per sample (mean n=2 samples) for the two different doses using the nasal cast setup described above. The tests in the nasal cast show that the nasal devices with 4-methylpyrozole result in an increase during the first hour and then a slower release up to the 24 hours tested.

[0188] As illustrated in Figure 14b, over the 8 hours tested, the total amount released from the 20 mg nasal device was 3234 pg 4-methylpyrozole. The total amount released from the 10 mg nasal device was 327 pg 4-methylpyrozole. Half of this amount is delivered at around 2 hours. The cumulative amounts show a proportionality of 1:10 which is interesting (i.e. it should be 1:20). This could indicate that the nasal devices are saturated at the surface at a level of 1:10.

[0189] The output rate, as seen in Figure 14a, shows the highest value at the first sampling point (30 minutes). It appears that after about 24h almost all 4-methylpyrozole has left the plugs.

[0190] As mentioned, the nasal cast used is divided into three nose parts ("Nose-front", Nose-mid" and "Nose-end"), corresponding to the front- mid-, and back section of the nasal cavity, followed by three sequential filters, to catch any remaining substance in the flowing air. The filters correspond to the airways behind the nasal cavity and into the lungs. Table 3 shows the distribution of captured 4-methylpyrozole in the different parts of the setup (% of total amount). The mean of all measurements for the 1 mg strength (second row in Table 3) are compared to that of the 20 mg strength (third row in Table 3).

[0191] Table 3.

[0192] As seen in Table 3, about 70% of the delivered amount stays in the nasal tract for lmg nasal devices and 60% for the 20mg product. The middle part of the nasal tract collects about half of the total nasal amount. Also of interest is that the nose to filter ratio of the amount found in the lmg plugs is higher than for the 20 mg plugs. This would perhaps indicate that the nose has also reached saturation at the 1 mg level.

[0193] Example 6 - testing release of memantine from a nasal device comprising memantine into a nasal cast

[0194] Memantine is a drug used for treatment of e.g. dementia, memory loss and Alzheimer's disease and is a NMDA receptor antagonist.

[0195] To evaluate the amount of memantine released from nasal devices comprising memantine, quantification was performed using a LC-MS analytical method. A Phenomenex Luna Omega C18 100A 2,1x50 mm columns was used. Mobile phase: water-MeCN - formic acid (95 : 5 : 0,1 v / v)„ Pump flow 0,3 mL / min, Injection volume 5pL).

[0196] Nasal devices comprising 20 mg memantine per device were tested. The nasal devices were manufactured essentially according to the nasal device A in Example 1, except that memantine was used instead of nicotine.

[0197] As in previous examples, a nasal cast divided into three different parts was used to mimic the nasal cavity. The inside of the nasal cast was coated with a gel comprising Brij / glycerol solution+ 0.05M Sulphuric acid, to mimic the nasal cavity membranes. Tests using the nasal cast were performed by arranging the nasal device to be tested in the cast in a closed air flow path. To also collect any tested substance able to pass through the nasal cast, three sequentially arranged filters (Bacterial filters were coated with 0.2M oxalic acid) similar to those used in Example 3 were arranged in the air flow following the nasal cast. 7.5 L / min continuous flow was used. Quantification of the amount of tested substance was performed in the nasal cast gel and in the following filters. The amounts of tested substance in the nasal cast parts and in the three filters were dissolved at specified time intervals. The time intervals used were every 30min up to 4h after that every 60 min up to 8 hours and a final test at 24 hours.

[0198] The results of Example 6 tests are shown in Figures 15a and 15b. Only one run was performed. Figure 15a shows output rate in the nasal cast setup for a single sample of the tested dose using the nasal cast setup described above. Figure 15b shows accumulated output in air for a single sample of the tested dose using the nasal cast setup described above. The test in the nasal cast show that the nasal devices with memantine result in an increase during the first hours and then a slower release up to the 24 hours tested.

[0199] As illustrated in Figure 15b, over the 8 hours tested, the total amount released from the 20 mg nasal device was about 5000 pg memantine.

[0200] The output rate, as seen in Figure 15a, shows the highest value at the 60 minute sampling point. It appears that after about 24h almost all memantine has left the plugs.

[0201] As mentioned, the nasal cast used is divided into three nose parts ("Nose-front", "Nose-mid" and "Nose-end"), corresponding to the front- mid-, and back section of the nasal cavity, followed by three sequential filters, to catch any remaining substance in the flowing air. The filters correspond to the airways behind the nasal cavity and into the lungs. Table 4 shows the distribution of captured memantine in the different parts of the setup (% of total amount).

[0202] Table 4. As seen in Table 4, about 37% of the delivered amount stays in the nasal tract for the 20mg product. The middle part of the nasal tract collects about 73% of the total nasal amount.

[0203] Example 7 - testing release of valproic acid from a nasal device comprising valproic acid into a nasal cast

[0204] Valproic acid is a drug used for treatment of e.g. epilepsy, bipolar disorder and migraines.

[0205] To evaluate the amount of valproic acid released from nasal devices comprising valproic acid, quantification was performed using a LC-MS analytical method. Mobile phase: water-ethanol (50 : 50 v / v).

[0206] Nasal devices comprising 20 mg valproic acid per device were tested. The nasal devices were manufactured essentially according to the nasal device A in Example 1, except that valproic acid was used instead of nicotine.

[0207] As in previous examples, a nasal cast divided into three different parts was used to mimic the nasal cavity. The inside of the nasal cast was coated with a gel comprising Brij / glycerol solution+ 0.05M Sulphuric acid, to mimic the nasal cavity membranes. Tests using the nasal cast were performed by arranging the nasal device to be tested in the cast in a closed air flow path. To also collect any tested substance able to pass through the nasal cast, three sequentially arranged filters (Bacterial filters were coated with 0.2M oxalic acid) similar to those used in Example 3 were arranged in the air flow following the nasal cast. 7.5 L / min continuous flow was used. Quantification of the amount of tested substance was performed in the nasal cast gel and in the following filters. The amounts of tested substance in the nasal cast parts and in the three filters were dissolved at specified time intervals. The time intervals used were every 30min up to 4h after that every 60 min up to 8 hours and a final test at 24 hours. Only one run was performed.

[0208] The results of Example 7 tests are shown in Figures 16a and 16b. Only one run was performed. Figure 16a shows output rate in the nasal cast setup for a single sample of the tested dose using the nasal cast setup described above. Figure 16b shows accumulated output in air for a single sample of the tested dose using the nasal cast setup described above. The test in the nasal cast shows that the nasal devices with valproic acid result in an increase during the first hours and then a slower release up to the 24 hours tested.

[0209] As illustrated in Figure 16b, over 12 hours tested, the total amount released from the 20 mg nasal device was about 15000 pg valproic acid, half of this amount is delivered after 3,5 hours.

[0210] The output rate, as seen in Figure 16a, shows the highest value at the 30 minute sampling point. It appears that after about 24h almost all valproic acid has left the plugs.

[0211] As mentioned, the nasal cast used is divided into three nose parts ("Nose-front", "Nose-mid" and "Nose-end"), corresponding to the front- mid-, and back section of the nasal cavity, followed by three sequential filters, to catch any remaining substance in the flowing air. The filters correspond to the airways behind the nasal cavity and into the lungs. Table 5 shows the distribution of captured valproic in the different parts of the setup (% of total amount).

[0212] Table 5.

[0213] As seen in Table 5, about 77% of the delivered amount stays in the nasal tract for the 20mg product. The middle part of the nasal tract collects about 46% of the total nasal amount.

[0214] The person skilled in the art realizes that the present disclosure is not limited to the preferred embodiments described above. The person skilled in the art further realizes that modifications and variations are possible within the scope of the appended claims. Additionally, variations to the disclosed embodiments can be understood and effected by the skilled person in practicing the claimed disclosure, from a study of the drawings, the disclosure, and the appended claims.

Claims

CLAIMS1. A nasal device (1, 10, 61) for use in delivery of pharmaceutical substances, the nasal device (1, 10, 61) being adapted for insertion into a nostril of a human subject, wherein the nasal device (1, 10, 61) comprises a structural molded material and at least one composition, said composition comprising at least one pharmaceutical substance, and optionally other components such as a solvent, auxiliary substances and / or excipients, characterized in that said composition is evenly dispersed in the structural molded material, wherein said composition is composed to essentially maintain the pharmaceutical properties of the pharmaceutical substance during a production process for the nasal device, the process comprising heating to a temperature of at least about 150°C, and wherein said substance is adapted to be released in gaseous form from the nasal device at a rate and duration suitable for administration of the substance via the olfactory bulb, the trigeminal nerve, upper airways, nasal mucosa and / or a combination thereof.

2. The nasal device according to claim 1, wherein said composition or the substance comprised in the composition, exhibits a flashpoint of at least about 150 °C, or, for protein substances, at least about 60 °C.

3. The nasal device (1, 10, 61) according to claim 1 or 2, wherein at least one of the composition as a whole and the pharmaceutical substance comprised in the composition exhibits a vapor pressure of at least 0.001 + / - 0,0005 mmHg at 25 °C.

4. The nasal device (1, 10, 61) according to any of the preceding claims, wherein the composition comprises essentially only the pharmaceutical substance.

5. The nasal device (1, 10, 61) according to any of the preceding claims, wherein said composition is comprised in an oil-like or liquid form in the structural molded material.

6. The nasal device (1, 10, 61) according to claim 5, wherein the pharmaceutical substance of the composition has any of the following characteristics:a. it is in liquid form upon mixing with the material of the nasal device to be molded; or b. it is in solid form, such as a powder, and the composition, in which it is comprised in, is in liquid form, upon mixing with the material of the nasal device to be molded.

7. The nasal device (1, 10, 61) according to any preceding claim, wherein the composition has a melting point lower than about 100 degrees °C preferably lower than about 80 °C.

8. The nasal device (1, 10, 61) according to any preceding claim, wherein said pharmaceutical substance has a molecular mass within the interval of 50 to 10.000 g / mol.

9. The nasal device (1, 10, 61) according to claim 8, wherein said pharmaceutical substance has a molecular mass within the interval of 50 to 750 g / mol, or wherein said pharmaceutical substance has a molecular mass within the interval of 750 to 10.000 g / mol.

10. The nasal device (1, 10, 61) according to any preceding claim, wherein said pharmaceutical substance has a polar surface area within the interval of 50 to 500 A2, or 10-200 A2.

11. The nasal device (1, 10, 61) according to any one of claims 1-10 for use in delivery of the pharmaceutical substance, wherein the pharmaceutical substance is released in gaseous form from the nasal device and is primarily intended to be delivered to a target site in the body via the olfactory bulb, the trigeminal nerve, upper airways, nasal mucosa and / or a combination thereof.

12. The nasal device (1, 10, 61) according to claim 11, wherein the target site is in the central nervous system.

13. The nasal device (1, 10, 61) according to any one of claims 11 to 12, for any of the following applications: neonatal drug delivery, catastrophic medicine delivery, for patients having a neurodegenerative disease, for malnourished patients, cancer patients, patients in need of pain relief, patients in elderly care (which patients may have difficulties toswallow orally administered pills), patients having pinprick fear or fear for syringes (such as trypophobia), to avoid risk of overdosing the pharmaceutical substance.

14. The nasal device (1, 10, 61) according to any preceding claim, wherein the pharmaceutical substance is evenly dispersed in a structural molded material and comprises one or more of L-Dopa, codeine, oxytocin, lorazepam, desogestrel, progesterone, rimantadine, noxytiolin, L-(-)-menthol, dexfenfluramine, anethol, pentorex, fenfluramine, fomepizole, valproic acid, memantine, nicotine, iron, vitamins, cytizine, morphine, fentanyl, triptans, various vaccines, adrenaline, amphetamine, Zyprexa (olanzapine), carbamazepine, azelastine, fluticasonpropionate, mometasone, naloxone, xylometazoline, apomorphine, or any substance effective on the central nervous system, including anesthetics, anticonvulsants, antiemetics, anti-Parkinson agents, CNS stimulants, muscle relaxants, narcotic analgesics, nonnarcotic analgesics, and sedatives.

15. The nasal device (1, 10, 61) according to any of the preceding claims, wherein the pharmaceutical substance is comprised in the nasal device at a dosage of 0.01 to 500 mg per nasal device, or from 0.1 to 50 mg per nasal device.

16. The nasal device (1, 10, 61) according to any of the preceding claims, wherein the nasal device comprises a plurality of pharmaceutical substances, wherein the plurality of pharmaceutical substances are either comprised in the same composition, or are comprised in separate compositions.

17. A method for administration of a pharmaceutical composition comprising at least one pharmaceutical substance to a target site in the body of a subject via the olfactory bulb, the trigeminal nerve, upper airways, nasal mucosa, lungs and / or a combination thereof, wherein the pharmaceutical substance is released in gaseous form from a nasal device according to any of claims 1-16.

18. The method according to claim 17, wherein the pharmaceutical substance comprises one or more of L-Dopa, codeine, oxytocin, lorazepam, desogestrel, progesterone, rimantadine, noxytiolin, L-(-)-menthol, dexfenfluramine, anethol, pentorex, fenfluramine, fomepizole, valproic acid, memantine, nicotine, iron, vitamins, cytizine, morphine, fentanyl, triptans,various vaccines, adrenaline, amphetamine, Zyprexa (olanzapine), carbamazepine, azelastine, fluticasonpropionate, mometasone, naloxone, xylometazoline, apomorphine, or any substance effective on the central nervous system, including anesthetics, anticonvulsants, antiemetics, anti-Parkinson agents, CNS stimulants, muscle relaxants, narcotic analgesics, nonnarcotic analgesics, and sedatives.

19. The method according to claim 17 or 18, wherein a combinatory effect is obtained, wherein a quick effect is obtained by delivery via the olfactory bulb and / or the trigeminal nerve to the central nervous system, and a slow-release effect is obtained by delivery via the upper airways, nasal mucosa and / or lungs to the blood stream and subsequently to bodily organs.

20. The method according to any of claims 17 to 19, wherein the pharmaceutical substance, upon administration to a subject, exhibits an immediate peak output rate, measured after about 10 minutes - 2 hours, at its target site in the subject, and a slow-release output rate, measured at some point in time after a duration of 2 - 48 hours, at its target site in the subject, being in the interval of 10-25% of the immediate peak output rate.

21. The method according to any of claims 17 to 20, wherein the pharmaceutical substance, upon administration to a subject, exhibits a cumulative amount, at its target site in the subject, which is increasing but at a successively lower rate up to at least 8 hours.

22. The method according to any of claims 17 to 21, wherein at least 10, 20, 30, 40, 50, 60, 70, 80 or 90% of the pharmaceutical substance released from the nasal device and delivered to the body of the subject, is delivered to the body via the nasal cavity, of which at least 30, 40, 50, 60, 70, 80 or 90 % is delivered via the olfactory bulb and / or the trigeminal nerve.

23. A pharmaceutical composition comprising at least one pharmaceutical substance for use in administration of the substance to a target site in the body of a subject via the olfactory bulb, the trigeminal nerve, upper airways, nasal mucosa, lungs and / or a combination thereof, wherein the pharmaceutical substance released in gaseous form from a nasal device according to any of claims 1-16.

24. The pharmaceutical composition according to claim 23, wherein the pharmaceutical substance comprises one or more of L-Dopa, codeine, oxytocin, lorazepam, desogestrel, progesterone, rimantadine, noxytiolin, L-(-)-menthol, dexfenfluramine, anethol, pentorex, fenfluramine, fomepizole, valproic acid, memantine, nicotine, iron, vitamins, cytizine, morphine, fentanyl, triptans, various vaccines, adrenaline, amphetamine, Zyprexa (olanzapine), carbamazepine, azelastine, fluticasonpropionate, mometasone, naloxone, xylometazoline, apomorphine, or any substance effective on the central nervous system, including anesthetics, anticonvulsants, antiemetics, anti-Parkinson agents, CNS stimulants, muscle relaxants, narcotic analgesics, nonnarcotic analgesics, and sedatives.

25. The pharmaceutical composition according to claim 23 or 24, wherein a combinatory effect is obtained, wherein a quick effect is obtained by delivery via the olfactory bulb and / or the trigeminal nerve to the central nervous system, and a slow-release effect is obtained by delivery via the upper airways, nasal mucosa and / or lungs to the blood stream and subsequently to bodily organs.

26. The pharmaceutical composition according to any of claims 23 to 25, wherein the pharmaceutical substance, upon administration to a subject, exhibits an immediate peak output rate, measured after about 10 minutes - 2 hours, and a slow-release output rate, measured at some point in time after a duration of 2 - 48 hours, at its target site in the subject, being in the interval of 10-25% of the immediate peak output rate.

27. The pharmaceutical composition according to any of claims 23 to 26, wherein the pharmaceutical substance, upon administration to a subject, exhibits a cumulative amount, at its target site in the subject, which is increasing but at a successively lower rate up to at least 8 hours.

28. The pharmaceutical composition according to any of claims 23 to T1 , wherein, wherein at least 10, 20, 30, 40, 50, 60, 70, 80 or 90% of the pharmaceutical substance released from the nasal device and delivered to the body of the subject, is delivered to the body via the nasal cavity, of which at least 30, 40, 50, 60, 70, 80 or 90 % is delivered via the olfactory bulb and / or the trigeminal nerve.

29. A kit of nasal devices comprising more than one nasal device according to claims 1-16, intended for use in delivery of at least one pharmaceutical substance.

30. The kit of nasal devices according to claim 29, wherein the kit comprises at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20 different nasal devices with different compositions comprising at least one pharmaceutical substance and / or different doses of the same composition comprising at least one pharmaceutical substance.

31. A method for producing a nasal device for use in delivery of at least one pharmaceutical substance, the nasal device (1, 10, 61) being adapted for insertion into a nostril of a human subject, comprising the steps of: a. providing and mixing (i) a material for the nasal device to be molded and a pharmaceutical composition comprising at least one pharmaceutical substance, so that said composition and the substance comprised in the composition is evenly dispersed in the structural molded material; b. using the mixture of step (a) in a molding process to form nasal devices, wherein the mixture is exposed to a temperature of at least about 150°C; wherein said substance essentially maintains the pharmaceutical properties during the production process, and wherein said substance is released in gaseous form from the nasal device at a rate and duration suitable for administration via the olfactory bulb, the trigeminal nerve, upper airways, nasal mucosa and / or a combination thereof.

32. A computer program for use in delivery of a pharmaceutical substance according to the method of claims 17-22 using the nasal device of any of claims 1- 16, comprising instructions which, when executed on at least one processor, cause the at least one processor to provide guidance to a subject undergoing delivery of the pharmaceutical substance, and / or following up activities performed by said subject as part of said delivery of pharmaceutical substance.

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