NASAL APPLICATOR

Abstract

The present invention relates to a nasal applicator (100) for administering nasally at least one medical substance (S), in particular an analgesic, having a housing (2), respectively comprising or connected to: a substance reservoir (R) for holding a quantity of the substance (S); a requesting device (1) to be actuated by the user with the aim of calling forward a next application dose (D.sub.n) of the substance (S); a dispenser (3) for applying application doses (D.sub.0, D.sub.1, D.sub.2, . . . , D.sub.n1, D.sub.n, D.sub.n+1, . . . ) upon actuation of the requesting device (1) at a respective delivery time (tA.sub.0, tA.sub.1, tA.sub.2, . . . , tA.sub.n1, tA.sub.n, tA.sub.n+1, . . . ); a connection site (4a) for a nasal attachment (4), or a nasal attachment (4) or a nasal piece; an application device (17) for applying an application dose of the substance (S) through the connection site (4a) or the nasal attachment (4) or the nasal piece and/or out of the nasal applicator (100).

Claims

1. A nasal applicator (100) for the nasal administering of at least one medical substance (S), in particular an analgesic, said nasal applicator (100) comprising a housing (2) which respectively comprises, or is connected to, a substance reservoir (R) for comprising a quantity of the substance (S); a requesting device (1) to be actuated by the user with the aim of requesting a next application dose (D.sub.n) of the substance (S); a dispenser (3) for dispensing application doses (D.sub.0, D.sub.1, D.sub.2, . . . , D.sub.n1, D.sub.n, D.sub.n+1, . . . ) upon actuation of the requesting device (1) at a respective dispensing point of time (tA.sub.0, tA.sub.1, tA.sub.2, . . . , tA.sub.n1, tA.sub.n, tA.sub.n+1, . . . ); a connection site (4a) for a nasal attachment (4), or a nasal attachment (4) or a nasal piece; and an application device (17) for applying an application dose of the substance (S) through the connection site (4a) or the nasal attachment (4) or the nasal piece and/or out of the nasal applicator (100).

2. The nasal applicator (100) according to claim 1, further comprising a dose chamber (13) for temporarily receiving the application dose of the substance (S) held in the substance reservoir (R); and a loading device (15) for loading the dose chamber (13) with the application dose of the substance (S) from the substance reservoir (R).

3. The nasal applicator (100) according to claim 2, wherein the application device (17) is arranged for applying the application dose of the substance (S) present in the dose chamber (13) through the connection site (4a), the nasal attachment (4) or the nasal piece and/or out of the nasal applicator (100).

4. The nasal applicator (100) according to claim 2, wherein the application device (17) and/or the loading device (15) comprises an energy storage for mechanical energy or spring energy.

5. The nasal applicator (100) according to claim 1, wherein the application device (17) and/or the loading device (15) comprises a motor, preferably an electric motor (19).

6. The nasal applicator (100) according to claim 1, wherein the application device (17) and/or the loading device (15) comprises a spindle (21).

7. The nasal applicator (100) according to claim 6, wherein the motor is connected to the spindle (21).

8. The nasal applicator (100) according to claim 1, further comprising a mechanism for changing the capacity volume of the dose chamber (13) for the application dose of the substance (S).

9. The nasal applicator (100) according to claim 1, further comprising a second fluid chamber comprising a desiccant or a substance neutralizing agent.

10. The nasal applicator (100) according to claim 1, wherein the application device (17) and the loading device (15) comprise or consist of identical components.

11. The nasal applicator (100) according to claim 1, further comprising an electronic control device (9).

12. The nasal applicator (100) according to claim 11, wherein the electronic control device (9) is programmed to make the application device (17) move and/or apply at a plurality of speeds.

13. The nasal applicator (100) according to claim 11, wherein the electronic control device (9) is programmed to act on the mechanism for changing the capacity volume of the dose chamber (13).

14. The nasal applicator (100) according to claim 2, wherein the loading device (15) for loading the dose chamber (13) with the application dose of the substance (S) comprises at least one first one-way valve (23a) or check valve, and/or wherein the dose chamber (13) is limited by at least one first one-way valve (23a) or check valve.

15. The nasal applicator (100) according to claim 2, wherein the loading device (15) for loading the dose chamber (13) with the application dose of the substance (S) comprises at least one second one-way valve (23b) or check valve, and/or wherein the dose chamber (13) is limited by at least one second one-way valve (23b) or check valve, wherein the second check valve (23b) preferably comprises an opening direction being, with respect to the dose chamber (13), opposite to that of the first check valve (23a).

16. The nasal applicator (100) according to claim 1, further comprising: a locking device (5) for temporarily locking the dispenser (3) during a re-begin of locking period (T_vain.sub.1, T_vain.sub.2, . . . , T_vain.sub.n1, T_vain.sub.n, T_vain.sub.n+1, . . . ) that begins again at or after the respective dispensing point of time (tA.sub.0, tA.sub.1, tA.sub.2, . . . , tA.sub.n1, tA.sub.n, tA.sub.n+1, . . . ) of the dispensed application dose (D.sub.0, D.sub.1, D.sub.2, . . . , D.sub.n1, D.sub.n, D.sub.n+1, . . . ), the locking period (T_vain.sub.1, T_vain.sub.2, . . . , T_vain.sub.n1, T_vain.sub.n, T_vain.sub.n+1, . . . ) having a locking period begin (T_vain.sub.1_S, T_vain.sub.2_S, . . . , T_vain.sub.n1_S, T_vain.sub.n_S, T_vain.sub.n+1_S, . . . ) and a locking period end (T_vain.sub.1_E, T_vain.sub.2_E, . . . , T_vain.sub.n1_E, T_vain.sub.n_E, T_vain.sub.n+1_E, . . . )

17. The nasal applicator (100) according to claim 1, further comprising: a dose-detection device (7) for detecting the amount of the application dose (D.sub.0, D.sub.1, D.sub.2, . . . , D.sub.n1, D.sub.n, D.sub.n+1, . . . ) respectively dispensed by the dispenser (3) at the dispensing point of time (tA.sub.0, tA.sub.1, tA.sub.2, . . . , tA.sub.n1, tA.sub.n, tA.sub.n+1, . . . ).

18. The nasal applicator (100) according to claim 1, further comprising: a data storage (M) for storing at least the dispensing points of time (tA.sub.0, tA.sub.1, tA.sub.2, . . . , tA.sub.n1) of one or more already dispensed application doses (D.sub.0, D.sub.1, D.sub.2, . . . , D.sub.n1) and/or the amounts of these application doses (D.sub.0, D.sub.1, D.sub.2, . . . , D.sub.n1).

19. The nasal applicator (100) according to claim 1, further comprising: a detection device (11) at least for detecting an activation behavior of the user at an actuation point of time (tB.sub.n) relating to the requesting device (1) with the aim of applying a next or further application dose (D.sub.n).

20. The nasal applicator (100) according to claim 11, wherein the electronic control device (9) is further programmed to read data stored in the data storage (M); evaluate the user's actuation behavior detected by the detection device (11); predetermine, at a predetermination point of time (tV.sub.n), the amount of the next or the further application dose (D.sub.n) which may be delivered to the user at a next dispensing point of time (tA.sub.n) in the event that the user actuates the requesting device (1) outside a locking period (T_vain.sub.n), wherein the predetermination point of time (tV.sub.n) lies at or after the actuation point of time (tB.sub.n), and wherein the predetermination takes place considering the data read from the data storage (M), wherein this data encompasses at least a) the dispensing point of time (tA.sub.0, tA.sub.1, tA.sub.2, . . . , tA.sub.n1) of one or several of the already dispensed application doses (D.sub.0, D.sub.1, D.sub.2, . . . , D.sub.n1), or the elapsing time period between the one or the several dispensing point of time(s) (tA.sub.0, tA.sub.1, tA.sub.2, . . . , tA.sub.n1) of the already dispensed application doses (D.sub.0, D.sub.1, D.sub.2, . . . , D.sub.n1) and the dispensing point of time (tA.sub.n) lying after the next actuation point of time (tB.sub.n), on the one hand and/or b) the amount of one or of several of the already dispensed application doses (D.sub.0, D.sub.1, D.sub.2, . . . , D.sub.n1) on the other hand.

21. The nasal applicator (100) according to claim 20, wherein the data storage (M) further encompasses pharmacological, pharmacodynamic, pharmacometric and/or pharmacokinetic data concerning the substance (S) or other data associated with the substance, wherein the electronic control device (9) is further programmed for additional reading of data stored in the data storage (M) concerning the substance (S) or data associated with the substance (S), and wherein predetermining the next application dose (D.sub.n) of the substance (S) takes place with additional consideration of the additionally read data.

22. The nasal applicator (100) according to claim 20, wherein said electronic control device (9) is further programmed to cause or initiate the further steps of: dispensing the next application dose (D.sub.n) in the predetermined amount at the corresponding dispensing point of time (tA.sub.n) by the dispenser (3); and subsequently storing the amount, and/or a concentration resulting thereof, of the application dose of the dispensed next application dose (D.sub.n) in the data storage (M) and causing the locking device (5) to temporarily lock the dispenser (3) for a locking period (T_vain.sub.n+1), beginning from or after the dispensing point of time (tA.sub.n) of this next application dose (D.sub.n), the locking having a locking period begin (T_vain.sub.n+1_S) and locking period end (T_vain.sub.n+1_E) and/or storing the dispensing point of time (tA.sub.n) of the dispensed, next application dose (D.sub.n) in the data storage (M).

23. The nasal applicator (100) according to claim 22, wherein the electronic control device (9) is further programmed to carry out or prompt or intitiate the sequence of the further steps of claim 22 also in connection with one or several of the deliveries of further application doses (D.sub.n+1) subsequent to the next application dose (D.sub.n).

24. The nasal applicator (100) according to claim 23, wherein the electronic control device (9) is further programmed to read from the data storage (M) data encompassing e.g. PK curves (PK25, PK50) and/or models, and which map a temporal course between concentration (C(t)) in the body, in particular blood, of the patient, and to calculate a next maximum (C.sub.1max, C.sub.2max, C.sub.nmax) of the concentration (C(t)) based thereon.

25. The nasal applicator (100) according to claim 24, wherein the electronic control device (9) is further programmed, upon predetermining the amount of the next application dose (D.sub.n) based on data stored in the data storage (M), in particular PK curves (PK25, PK50) or models, and on a therapeutic maximum stored in the data storage (M), to determine the amount of the next application dose (D.sub.n) such that the next maximum (C.sub.1max, C.sub.2max, C.sub.nmax) will not exceed the specified maximum.

26. The nasal applicator (100) according to claim 20, wherein evaluating the detected actuation behavior of the user encompasses determining the actuation point of time (tB.sub.n) for requesting the next application dose (D.sub.n), or the time span lying between this actuation point of time (tB.sub.n) and the locking period end (T_vain.sub.n_E) of the last expired locking period (T_vain.sub.n); wherein predetermining encompasses considering the determined next actuation point of time (tB.sub.n) or the determined time span.

27. The nasal applicator (100) according to claim 9, further comprising a feedback device (8) to be actuated by the user; wherein the detection device (11) is programmed for detecting actuation of the feedback device (8) at least at one, preferably first, feedback point of time (tF.sub.n_1); wherein the control device (9) is programmed for determining the concentration of the substance (S) present in the body or in the blood of the user at the at least one feedback point of time (tF.sub.n_1), and for setting a target concentration (C.sub.ED) or its maximum value to a value respectively below the determined concentration.

28. The nasal applicator (100) according to claim 27, wherein the detection device (11) is further programmed for detecting at least one actuation of the requesting device (1) made by the user at actuation points of time (tB.sub.1, tB.sub.2, . . . , tB.sub.n1, tB.sub.n, tB.sub.n+1, . . . ) after the locking period (T_vain.sub.1, T_vain.sub.2, . . . , T_vain.sub.n1, T_vain.sub.n, T_vain.sub.n+1, . . . ) and/or for detecting a, preferably last, feedback point of time (tF.sub.n_4) after from which no further actuations of the feedback device (8) by the user have been detected; wherein the control device (9) is further programmed for determining both a concentration (C(t)) in the body, in particular in the blood, associated with the, preferably first, feedback point of time (tF.sub.n_1) as well as a concentration (C(t)) in the body, in particular in the blood, associated with the, preferably first, actuation point of time (tB.sub.1, tB.sub.2, . . . , tB.sub.n1, tB.sub.n, tB.sub.n+1, . . . ) or with the last feedback point of time (tF.sub.n_4), respectively; for determining a temporal concentration course, or a concentration course over time, from a group of temporal concentration courses, in particular models or PK curves (PK50.sub.+SD, PK50.sub.M und PK50.sub.SD), associated with the same dose, from a plurality of temporal concentration courses, in particular PK models or PK curves, associated with the same dose and stored in the data storage (M), while considering both the, preferably first, feedback point of time (tF.sub.n_1) and a concentration associated with the, preferably first, actuation point of time (tB.sub.1, tB.sub.2, . . . , tB.sub.n1, tB.sub.n, tB.sub.n+1, . . . ) or with the last feedback point of time (tF.sub.n_4); and for considering the temporal individual concentration course determined in this way, in particular the determined individual PK curve (PK.sub.Ind), upon predetermining the amount of one or several of the subsequent application doses (D.sub.3, D.sub.n, D.sub.n+1, . . . ).

29. The nasal applicator (100) according to claim 27, wherein the control device (9) is further programmed for considering, upon predetermining the amount of the next application dose (D.sub.n), the specified target concentration (C.sub.ED) or its maximum value and/or the determined temporal individual concentration course, in particular the determined individual PK curve (PK.sub.Ind).

30. The nasal applicator (100) according to claim 9, wherein the control device (9) is further programmed for determining, after the dispensing of an initial dose (D.sub.0) which was dispensed at a dispensing point of time (tA.sub.0) at or for a first actuation point of time (tB.sub.1) which lies after the dispensing point of time (tA.sub.0) of the initial dose (D.sub.0), respectively, a concentration (C.sub.ED1_+SD, C.sub.ED1_M, C.sub.ED1_SD) associated with the first actuation point of time (tB.sub.1), and for setting the concentrations (C.sub.ED1_+SD, C.sub.ED1_M, C.sub.ED1_SD) determined in this way, respectively, as the estimated target concentration of the associated temporal concentration course, wherein said determining is for a group of temporal concentration courses, in particular models or PK curves (PK50.sub.+SD, PK50.sub.M and PK50.sub.SD) which are associated with the same dose from a plurality of temporal concentration courses, in particular PK models or PK curves, which are stored in the data storage (M) and are associated with the same dose; for applying the first application dose (D.sub.1) following the initial dose (D.sub.0) in response to the actuation of the requesting device (1) at the first actuation point of time (tB.sub.1); for determining, for the temporal concentration courses of the group, at which time after the application of the first application dose (D.sub.1) the concentration in the body, in particular in the blood, will, respectively, have dropped again to the estimated target concentration of the associated temporal concentration course, and for setting, respectively, for the temporal concentration courses of the group, the determined time as the calculated target concentration time (tB.sub.2_+SD, tB.sub.2_M, tB.sub.2_SD); for detecting or determining the second actuation point of time (tB.sub.2) for requesting a second or subsequent application dose (D.sub.2); for determining a temporal concentration course from the group as an individual temporal concentration course, in particular as an individual PK curve (PK.sub.Ind), while considering the respective difference between the calculated target concentration time (tB.sub.2_+SD, tB.sub.2_M, tB.sub.2_SD) of each temporal concentration course from the group and the second actuation point of time (tB.sub.2), in particular the temporal concentration course which has the smallest difference between its calculated target concentration time (tB.sub.2_+SD, tB.sub.2_M, tB.sub.2_SD) and the second actuation point of time (tB.sub.2); and for considering the determined temporal individual concentration course, in particular the determined individual PK curve (PK.sub.Ind), upon predetermining the amount of one or several of the subsequent application doses (D.sub.3, D.sub.n, D.sub.n+1, . . . ).

31. The nasal applicator (100) according to claim 9, wherein the control device (9) is further programmed for determining the concentration of the substance (S) present in the body or blood of the user at least at one considered actuation point of time (tB.sub.n1) or at least one considered predetermination point of time (tV.sub.n1), and for setting this concentration as the target concentration (C.sub.ED); and wherein the control device (9) is further programmed for setting, at the next predetermination point of time (tV.sub.n), the amount of the next application dose (D.sub.n) such that the concentration in the body or in the blood of the user decreases again to the target concentration (C.sub.ED) only after a predetermined time period has elapsed, beginning from the dispensing point of time (tA.sub.n) of the next application dose (D.sub.n).

32. The nasal applicator (100) according to claim 1, wherein the evaluation of the actuation behavior of the user detected by the detection device (11) encompasses detecting actuations of the requesting device (1) by the user at actuation points of time (tB.sub.1_v1, tB.sub.2_v1, tB.sub.1_v2, tB.sub.2_v2) within one of the locking periods (T_vain.sub.1, T_vain.sub.2, . . . , T_vain.sub.n1, T_vain.sub.n, T_vain.sub.n+1, . . . ); the control device (9) is further programmed for determining a concentration (C(t)) in the body, in particular in the blood, associated with the actuation points of time (tB.sub.1_v1, tB.sub.2_v1, tB.sub.1_v2, tB.sub.2_v2) within one of the locking periods (T_vain.sub.1, T_vain.sub.2, . . . , T_vain.sub.n1, T_vain.sub.n, T_vain.sub.n+1, . . . ), respectively; setting the target concentration (C.sub.ED) or its minimum value to a value respectively above the associated concentration (C(t)).

33. The nasal applicator (100) according to claim 32, wherein the detection device (11) is further programmed for detecting at least one actuation of the requesting device (1) by the user at actuation points of time (tB.sub.1, tB.sub.2, . . . , tB.sub.n1, tB.sub.n, tB.sub.n+1, . . . ) after the locking period (T_vain.sub.1, T_vain.sub.2, . . . , T_vain.sub.n1, T_vain.sub.n, T_vain.sub.n+1, . . . ); wherein the control device (9) is further programmed for determining a concentration (C(t)) in the body, in particular in the blood, associated with the actuation point of time (tB.sub.1, tB.sub.2, . . . , tB.sub.n1, tB.sub.n, tB.sub.n+1, . . . ) after the locking period (T_vain.sub.1, T_vain.sub.2, . . . , T_vain.sub.n1, T_vain.sub.n, T_vain.sub.n+1, . . . ), respectively; for determining a temporal concentration course of the group while considering both at least one, preferably the last, actuation point of time (tB.sub.1_v1, tB.sub.2_v1, tB.sub.1_v2, tB.sub.2_v2) within the locking period (T_vain.sub.1, T_vain.sub.2, . . . , T_vain.sub.n1, T_vain.sub.n, T_vain.sub.n+1, . . . ) as well as at least one, preferably the first, actuation point of time (tB.sub.1, tB.sub.2, . . . , tB.sub.n1, tB.sub.n, tB.sub.n+1, . . . ) after the locking period (T_vain.sub.1, T_vain.sub.2, . . . , T_vain.sub.n1, T_vain.sub.n, T_vain.sub.n+1, . . . ); and for considering the determined temporal individual concentration course, in particular the determined individual PK curve (PK.sub.Ind), upon predetermining the amount of one or several of the subsequent application doses (D.sub.3, D.sub.n, D.sub.n+1, . . . ).

34. The nasal applicator (100) according to claim 1, wherein the evaluation of the actuation behavior of the user detected by the detection device (11) encompasses evaluating the actuations of the requesting device (1) by the user at actuation points of time (tB.sub.1_v1, tB.sub.2_v1, tB.sub.1_v2, tB.sub.2_v2) within one of the locking periods (T_vain.sub.1, T_vain.sub.2, . . . , T_vain.sub.n1, T_vain.sub.n, T_vain.sub.n+1, . . . ); the control device (9) is further programmed for determining an increase in the time intervals between successive actuation points of time (tB.sub.1_v1, tB.sub.2_v1, tB.sub.1_v2, tB.sub.2_v2) within one of the locking periods (T_vain.sub.1, T_vain.sub.2, . . . , T_vain.sub.n1, T_vain.sub.n, T_vain.sub.n+1, . . . ) or the absence of further actuation points of time (tB.sub.1_v1, tB.sub.2_v1, tB.sub.1_v2, tB.sub.2_v2) within the locking period (T_vain.sub.1, T_vain.sub.2, . . . , T_vain.sub.n1, T_vain.sub.n, T_vain.sub.n+1, . . . ), and for defining a point of time starting from which the degree of increase or the absence satisfies predetermined criteria; the control device (9) is further programmed for determining a concentration (C(t)) in the body, in particular in the blood, associated with the defined set point of time; setting the target concentration (C.sub.ED) or its minimum value to a value above the associated concentration (C(t)), respectively.

35. The nasal applicator (100) according to claim 34, wherein the control device (9) is further programmed for evaluating at least one detected actuation of the requesting device (1) by the user at actuation points of time (tB.sub.1, tB.sub.2, . . . , tB.sub.n1, tB.sub.n, tB.sub.n+1, . . . ) after the locking period (T_vain.sub.1, T_vain.sub.2, . . . , T_vain.sub.n1, T_vain.sub.n, T_vain.sub.n+1, . . . ); wherein the control device (9) is further programmed for determining a concentration (C(t)) in the body, in particular in the blood, associated with the actuation point of time (tB.sub.1, tB.sub.2, . . . , tB.sub.n1, tB.sub.n, tB.sub.n+1, . . . ) after the locking period (T_vain.sub.1, T_vain.sub.2, . . . , T_vain.sub.n1, T_vain.sub.n, T_vain.sub.n+1, . . . ), respectively; for determining a temporal concentration course of the group while considering both a, preferably the last, actuation point of time (tB.sub.1_v1, tB.sub.2_v1, tB.sub.1_v2, tB.sub.2_v2) within the locking period (T_vain.sub.1, T_vain.sub.2, . . . , T_vain.sub.n1, T_vain.sub.n, T_vain.sub.n+1, . . . ) as well as a, preferably the first, actuation point of time (tB.sub.1, tB.sub.2, . . . , tB.sub.n1, tB.sub.n, tB.sub.n+1, . . . ) after the locking period (T_vain.sub.1, T_vain.sub.2, . . . , T_vain.sub.n1, T_vain.sub.n, T_vain.sub.n+1, . . . ); and for considering the determined temporal individual concentration course, in particular the determined individual PK curve (PK.sub.Ind), upon predetermining the amount of one or several of the subsequent application doses (D.sub.3, D.sub.n, D.sub.n+1, . . . ).

36. A system comprising one or more nasal applicators (100) according to any one of the preceding claims; one or more peripheral devices (101); wherein the one or the several nasal applicators (100) are, or are prepared or are programmed to be in signal communication or in communication connection with one or with several of the peripheral devices (101).

Description

[0565] In the following, the invention is described based on exemplary embodiments thereof with reference to the accompanying drawing. In the figures, the following applies:

[0566] FIG. 1 shows a nasal applicator as an example of a drug dispensing device of a first exemplary embodiment, as well as a system according to the present invention;

[0567] FIG. 2 shows schematically and exemplarily a possible temporal course of a use of the nasal applicator according to the present invention as an example of a drug dispensing device;

[0568] FIG. 3 shows schematically and exemplarily the amount of the cumulative doses of different applications of a substance to the user;

[0569] FIG. 4 shows schematically and exemplarily the result of a predetermination of the amount of the different application doses;

[0570] FIG. 5a shows schematically and based on three exemplarily selected temporal concentration courses, the determining of an individual concentration course for a considered user of the nasal applicator according to the present invention

[0571] FIG. 5b shows a continuation of the idea of FIG. 5a underlying in some embodiments the present invention; and

[0572] FIG. 6 shows a nasal applicator of a further exemplary embodiment.

[0573] FIG. 1 shows a nasal applicator 100 of a first exemplary embodiment in a schematically simplified representation.

[0574] As shown in FIG. 1, the nasal applicator 100 comprises a housing 2 in or on which optionally one, all or several of the devices or components mentioned below may be independently arranged. In other embodiments, one or several of these components may in any combination be present externally, i.e., not within the housing 2.

[0575] The nasal applicator 100 comprises a requesting device 1, which the user has to actuate in order to be able to apply to themselves a dose D (see FIG. 2 or 3) of a substance S from a substance reservoir R. The substance S may be a medical or non-medical agent, in particular an analgesic. The requesting device 1 may at the same time be, or comprise, an optionally provided feedback device 8. The feedback device 8, if provided, may alternatively be a stand-alone device.

[0576] If the user has actuated the requesting device 1, which may be a switch, a button, an insert or similar, and thus triggered an actuation signal, a dispenser 3 may release a quantity of substance S which has been dosed by the dispenser, i.e. determined in terms of quantity or volume. It may flow, be injected, or similar, out of the substance reservoir R via the lumen of a nasal attachment 4 which is to be inserted into a nostril into the user's nose. It may alternatively be applied out of the substance reservoir R via a droplet generator which may be part of the nasal attachment 4 or another or different device of the nasal applicator 100 into the nose.

[0577] A display 12, e.g. display, LED, etc., in particular optical or haptic, can be provided.

[0578] In addition or supplementary to an optical display, an acoustic indicator, such as a loudspeaker, buzzer, beeper, a haptic indicator, e.g. by vibration, or similar may be provided.

[0579] For this purpose, the substance reservoir R may optionally be acted upon by an energy loading mechanism or by another application device, see e.g. FIG. 6. This may work with pressure, force, speed, oscillation, vibration, rotation, electrical/magnetic forces, etc. The latter forces or physical events may, for example, influence the release speed, the force, the pressure, the acceleration, the flow rate, and thus the parameters of the application device, e.g., a droplet generator, i.e., influence the result of the droplet generator. The droplet generator, which may for example be part of the dispenser 3 or the nasal attachment 4, may thus for example be a pressurization mechanism acting on the substance S; for example, a piston pushes into the substance reservoir R, or a pump draws from the substance reservoir R and loads the substance S with pressure, force, speed, etc. and pushes it through the droplet generator.

[0580] The optional droplet generator may work mechanically and/or electrically. It may be designed e.g. as a nozzle, vaporizer, piezo element, etc., or comprise similar. It may preferably generate a spray or a cloud of droplets or a cloud of particles.

[0581] If such a release by the dispenser 3 is not possible at any points in time and not due to each actuation of the requesting device 1 and/or at any points in time thereof, a locking device 5 may optionally be provided. It is preferably configured to prevent, not allow, etc., preferably time-controlled, a release or a discharge or a delivery by the dispenser 3 during a defined locking period (see, for example, T_vain.sub.n in FIG. 2) determined according to predetermined criteria with respect to its duration and/or the point of time of its begin and/or end, even if the requesting device 1 should be actuated during the locking period. During the locking period, which in several embodiments is of fixed or invariable duration, while in others it is variable or changeable, an actuation of the requesting device 1 generally or in principle does not lead to an application, whereas this need not to, or does not, apply to an actuation after the locking period has expired.

[0582] The amount or volume of that part of the substance S which is delivered and/or has been delivered in individual initial doses or application doses (D.sub.0, D.sub.1, D.sub.2, . . . , D.sub.n, . . . in FIG. 2 or in FIG. 3) as explained below at different dispensing points of time tA.sub.0, tA.sub.1, tA.sub.2, . . . , tA.sub.n, . . . may be detected by an optional dose-detection device 7.

[0583] The dose-detection device 7 may be configured to measure, determine, store, sum up, etc., the individual initial doses or application doses D.sub.0, D.sub.1, D.sub.2, . . . , D.sub.n, . . . , which have been delivered by the nasal applicator 100 and which are variable, i.e. not fixed dose amounts.

[0584] The dose-detection device 7 may, for example, measure a quantity, a volume or another parameter which allows a direct statement about the respective application dose. The dose-detection device 7 may additionally or alternatively measure or determine a parameter which allows an indirect statement about the respective application dose, such as a flow per time, a number of strokes of a pump, a number of revolutions of a pump, or similar.

[0585] The dose-detection device 7 or another device, such as the electronic control device 9, may be configured to detect for example the release parameters e.g. the speed, acceleration, force, displacement, etc. Such detected or determined values are optionally stored.

[0586] Dose limits and/or concentration limits, which restrict a total dose and/or total concentration limited or predetermined e.g. in relation to a unit of time, can optionally be provided.

[0587] The dose-detection device 7 may, if present, additionally or alternatively be programmed to record a point in time at which one or more specific application doses were or are administered by the nasal applicator 100. The dose-detection device 7 may further be additionally or alternatively programmed to detect a time period, for example between two or more dispensing points of time tA.sub.0, tA.sub.1, tA.sub.2, . . . , tA.sub.n, . . . (see FIG. 2 or FIG. 3) of administered initial doses or application doses D.sub.0, D.sub.1, D.sub.2, . . . , D.sub.n, . . . . Further periods of time between any points of time mentioned herein may also be detected (e.g., tA.sub.1/minus T_vain.sub.1_E, tA.sub.1 (in particular last) tB.sub._v, tB.sub.1_v1tA.sub.0, tB.sub._v (in particular the last one, i.e. tB.sub._v-1)tA.sub.0, T_vain.sub.1_Elast tB.sub._v, T_vain.sub.1_EtB.sub.1_v1, whose parameters are explained below).

[0588] An electronic control device 9 can optionally be provided in order to control, regulate and/or monitor the function of the nasal applicator 100 or several, any or all of the devices or components mentioned with reference to FIG. 1. It may be provided within the housing 2 or externally, as set forth above. Purely exemplarily, it may be the recipient of information about initial doses or application doses D.sub.0, D.sub.1, D.sub.2, . . . , D.sub.n, . . . , which have been predetermined externally. Corresponding wired or wireless signal communications may be provided, uni-directional or bi- or multi-directional, between the control device 9 and the component or components of the nasal applicator 100

[0589] An optional detection device 11 may be provided in order to detect whether, that and/or when the user, who may be herein a user, operator or patient, attempted or initiated to apply themselves a further application dose by actuating the requesting device 1.

[0590] In each embodiment, the substance reservoir R may optionally be interchangeable, for example, as a single-shot reservoir, a substance reservoir having sufficient substance S for a plurality of application procedures, etc.

[0591] The substance reservoir R may be for example pre-filled, self-fillable, integrated, replaceable, designed for single application, and/or designed for multiple application.

[0592] The substance reservoir R may be arranged inside the housing 2 or externally thereto.

[0593] The substance S may have any state of aggregation (liquid, gaseous, solid, etc.).

[0594] An optional data storage M for storing data, or with data stored herein, may be arranged inside the housing 2 or externally thereto.

[0595] These data may relate to the previous use of the nasal applicator 100 by the user, as well as time data for the points of time or time periods (synonymously: time intervals) mentioned herein, etc.; they may be the result of an evaluation by the control device 9, etc., or optionally be data for pharmacological, pharmacodynamic, pharmacometric and/or pharmacokinetic data concerning the substance S and/or underlying medical circumstances such as the basic disease, etc. They may be substance-related and/or defined by the physician or other authorized persons, e.g., a t.sub.max value of substance S, a physician-corrected, so-called overruled t.sub.max value, e.g., the point of time or the end of the time interval after application at which or in which the maximum concentration or blood concentration occurs, the half-life, the terminal half-life, a value adjusted by the physician or by other authorized persons, etc.

[0596] The data may be objective and/or subjective.

[0597] The data may be objective values (sensor values), e.g. blood glucose level, blood pressure, heart rate, respiratory rate, oxygen saturation, etc.

[0598] The data may be subjective values (effect values), which cannot be measured directly. They are derived based on collected values such as pain score, sedation score, side effects, etc.) and/or measured values (e.g., SpO.sub.2, HR, HRV, etc.).

[0599] Data may be, or encompass, recommended concentration, contraindications, side effects, expiration date, and/or package insert, professional or expert information, patient information, Summary of Product Characteristics (SmPC), assembly instructions, disassembly instructions, operating instructions/manuals, etc.

[0600] The data may optionally include, in addition to pharmacological and/or pharmacokinetic data, user-related data such as weight, age, gender, BMI, pre-existing conditions, comedications, comorbidities, allergies, etc. Generally, the user history and/or treatment history are encompassed (e.g., data on prior interventions, procedures, diagnoses, medical histories, tests, medications received/prescribed, anesthetics received, muscle relaxants, antiemetics, etc.).

[0601] Such and other data may help the optional control device 9 to calculate more accurate dosages, or to increase the safety of the therapy.

[0602] Such and other data may relate to release parameters, e.g. those required to obtain a defined droplet size distribution.

[0603] Trigger parameters may vary depending on the predetermined dose. It may be set for example by the releasing speed of the application device.

[0604] The optional data storage M may be a hardware memory device, a flash memory or an external data storage, for example arranged in a cloud, in a mobile device or the like and/or be in signal communication with further components of the nasal applicator 100 via Wi-Fi/Bluetooth, etc.

[0605] The locking device 5 and/or the detection device 11 are preferably components realized or implemented electronically, for example by the control device 9.

[0606] A timer or chronometer, such as a clock, may be provided. The individual components, as mentioned above, may make use of it.

[0607] By using the chronometer, for example an absolute time measurement (i.e., based on the correct/real/current time) may be optionally carried out or a relative time measurement, in which, preferably when the nasal applicator is initialized or switched on for the first time, a current time stamp is detected, by which the time may be determined back.

[0608] It may be provided in some embodiments to inform the user about the expiration of the current locking period, for example visually or acoustically or haptically, such as by vibration.

[0609] Since a number of peripheral devices 101 are indicated in FIG. 1, this figure also shows a system according to the present invention.

[0610] The peripheral devices 101 may have the same design or configuration, or, at least several of them, may differ from each other.

[0611] For example, some of the peripheral devices 101 may be nasal applicators optionally configured as the nasal applicator 100, and/or configured as a docking station, a server, a smart device, etc., preferably as described herein.

[0612] Optionally, some or all of the peripheral devices 101 may or may not communicate with or among each other in any combination.

[0613] In FIG. 1, it is indicated that they may all also communicate with the nasal applicator 100, but this is also optional. In some embodiments, only some of the peripheral devices 101 can do this.

[0614] Further, it may optionally be provided that the nasal applicator 100 and/or the peripheral devices 101 may communicate externally via the nasal applicator 100 and/or the docking station and/or another peripheral device 101.

[0615] The substance reservoir R may be connected by, e.g., Luer lock, pin, needle, spike with or without aeration, etc.

[0616] A filter (e.g., a 22 m particle filter), e.g., made of or containing activated carbon, plastic fibers, or similar, or a porous membrane (e.g., a Porex filter) may be provided. This filter may be provided at the outlet of the dose chamber. More than one filter may be provided.

[0617] The substance reservoir R may comprise a plug that can move up. This enables a position-independent release by the nasal applicator 100.

[0618] All materials may be inert or partially inert, e.g. made of or with silicone, glass, cyclo olefin polymer (COP), cycloolefin copolymers (COC), etc.

[0619] The substance reservoir R may have a pierceable membrane, a screw connection, a push-fit/in connection, a quick connection, etc.

[0620] The substance reservoir may comprise a riser tube.

[0621] The substance reservoir R may be e.g. a pouch bottle (bag-in-bottle), a bag (as in infusions) or another container which may collapse and does not require air to flow into the container. With such solutions, one may release not depending on the position, i.e. in any spatial orientation of the nasal applicator 100.

[0622] FIG. 2 shows schematically and exemplarily a possible temporal course of a use of the nasal applicator 100 according to the present invention.

[0623] If the user actuates the requesting device 1 in order to apply to themselves, for example, an application dose D.sub.n referred to herein as the next application dose, then it is determined by the electronic control device 9 or by its detection device 11 whether or not this point of time at which the user wishes to apply to themselves this next application dose D.sub.n possibly falls within a locking period T_vain.sub.n which is still ongoing.

[0624] If this time, at which the requesting device 1 is actuated, falls within the locking period T_vain.sub.n, then no application dose D.sub.n is applied to the user at said time in any case. Such points of time are shown in FIG. 2 with reference to an earlier locking period T_vain.sub.1 exemplarily as points of time tB.sub.1_v1 and tB.sub.2_v1 with reference to further locking periods, e.g. as tB.sub.1_v2, and are optionally included in the predetermination.

[0625] If, on the other hand, the point of time of actuation of the requesting device 1 does not fall within the locking period T_vain.sub.n, but is after the expiration or end T_vain.sub.n_E of the locking period T_vain.sub.n, as shown in the example of FIG. 2 on the basis of the actuation point of time tB.sub.n, then the next application dose D.sub.n is applied to the patient at a point of time designated herein as the next dispensing point of time tA.sub.n.

[0626] Prior to the application of the next application dose D.sub.n, its amount is defined or predetermined by the electronic control device 9 at a, herein designated as next, predetermination point of time tV.sub.n; corresponding calculations may have been performed by the control device 9 itself or it may have accepted results of such calculations.

[0627] The predetermination of the amount of the next application dose D.sub.n is determined by the nasal applicator 100 or its components mentioned with regard to FIG. 1, such as the control device 9, regardless of whether they are included in the housing 2 of the nasal applicator 100 or are external thereto.

[0628] The first predetermination point of time tV.sub.n, like the actuation point of time tB.sub.n, may lie at or before the first dispensing time tA.sub.n; it may therefore coincide with the first dispensing point of time tA.sub.n, at least within the scope of what is technically possible, so that there is sufficient time remaining between the first predetermination point of time tV.sub.n and the next dispensing point of time tA.sub.n for actually predetermining or calculating the amount of the next application dose D.sub.n and time for addressing the devices or components, to which the predetermined amount before application must be communicated by signal or in some other way.

[0629] Upon predetermining the amount of the next application dose D.sub.n, which is an example of the variable dose D, i.e. it is just not or not exclusively preset for the nasal applicator 100 in an unchangeable manner by physician or other authorized persons, manufacturer or similar, then data readable from the data storage M and/or data determined by the components of the nasal applicator 100 mentioned in FIG. 1 may be taken into account.

[0630] This data preferably already includes an initial point of time tA.sub.0 prior to the successful actuation point of time tB.sub.n, at which point of time an initial dose D.sub.0 may possibly have been administered to the user even before delivery of the first application dose D.sub.1, whether by the nasal applicator 100 according to the present invention, by medical personnel, e.g. while still in a post-operative recovery room, etc. Further, this data may include the amount of this optional initial dose D.sub.0.

[0631] In the present case, it is assumed that an initial dose D.sub.0 was delivered to the user at an initial point of time tA.sub.0.

[0632] This data preferably includes any initial time tA.sub.0, tA.sub.1, tA.sub.2, tA.sub.n1, prior to the successful actuation point of time tB.sub.n, at which an initial dose or application dose D.sub.0, D.sub.1, D.sub.2, D.sub.n1 had already been administered to the user or at which they had administered a dose to themselves. Alternatively or additionally, the time elapsed since then and preferably also the respective amount of the above-mentioned doses are also included.

[0633] When considering the planned delivery of the next application dose D.sub.n, these data include, for example, at least the amount of the previous application dose D.sub.n1 and, optionally, its dispensing point of time tA.sub.n1 or the time elapsed since then.

[0634] The predetermination, which takes place at the first predetermination point of time tV.sub.n, thus results in the amount of the next application dose D.sub.n. There is determined the amount at the next predetermination point of time tV.sub.n, which is after the next actuation point of time tB.sub.n and is not preset by a physician or other authorized persons, manufacturer or similar, which may also apply to all or some of the further application doses mentioned herein. The predetermination at the next predetermination point of time tV.sub.n is performed taking into account data read from the data storage M.

[0635] After the next application dose D.sub.n has been applied, a locking period T_vain.sub.n is set and/or begun again, preferably at the dispensing point of time tA.sub.n of the next application D.sub.n. It may have the same length as previous or subsequent locking periods, or deviate from them. The length of the respective locking period may be predetermined and/or set, for example, by the physician or other authorized persons. When setting the next locking period, a logic or an algorithm may be followed for which it may be calculated at each predetermination point of time tV.sub.n.

[0636] As can be seen from FIG. 2, the procedure described above for this figure may be repeated.

[0637] Upon predetermining the amount of an application dose D.sub.n+1 after the next one, in addition to the amounts and/or the dispensing points of time of the aforementioned application doses and possibly also of the initial dose D.sub.0, the amount and/or the application time t.sub.An of the application dose D.sub.n designated herein as the next application dose, but then already applied, may now however optionally be taken into account for the first time, wherein the amount and/or the application time t.sub.An of the application dose D.sub.n may be detected in the meantime as data and likewise kept in the data storage M.

[0638] The predetermination of the amount of the application dose D.sub.n+1 after the next one, which takes place at the predetermination point of time tV.sub.n+1, may therefore now also take into account the length of the time span that lies between the dispensing point of time tA.sub.n+1 after the next one and the next dispensing point of time tA.sub.n as well as the lengths of the time spans that lie between the dispensing point of time tA.sub.n+1 after the next one and the initial time tA.sub.0 or earlier dispensing points of time tA.sub.1, tA.sub.2.

[0639] FIG. 3 shows schematically and exemplarily the applied individual doses D.sub.0, D.sub.1, D.sub.2, . . . , D.sub.n1, D.sub.n, D.sub.n+1, . . . and the doses of substance S accumulated over the course of time t, whose amounts and/or dispensing points of time tA.sub.0, tA.sub.1, tA.sub.2, . . . , tA.sub.n1, tA.sub.n, tA.sub.n+1, . . . etc. may be included in the predetermination of respective later application doses.

[0640] The time axis t as well as its scaling correspond to the one used in FIG. 2 or may be assumed to be identical. The point of time tA.sub.1 and the point of time tA.sub.2 thus correspond to the absolute points of time tA.sub.1 and tA.sub.2 shown in FIG. 2.

[0641] FIG. 4 describes schematically and exemplarily the phase of supplying the substance S to the user, also referred to herein as the titration phase (which is a finding phase or a determination phase), in which the target concentration prompting the therapeutic effect being desired by the user is determined. The amount of the following application doses may then be determined thereupon and/or an individual, dose- or concentration-based treatment plan may be set up in a time-controlled manner.

[0642] Curves such as those shown in FIG. 4 or elsewhere herein may be generated based on, for example, the discussion by Dubois, A., Bertrand, J., & Mentr, F. (2011) in Mathematical expressions of the pharmacokinetic and pharmacodynamic models implemented in the PFIM software. UMR738, INSERM, Paris Diderot University. The control device may be programmed to generate such curves and/or to perform the calculations required therefor. The contents of that publication are hereby made by reference the subject-matter of the present disclosure as well.

[0643] FIG. 4 shows schematically and by exemplarily the result of a predetermination of the amount of the various application doses D.sub.1, D.sub.2 and further, each of which may be an example of the respective next application dose D.sub.n as used herein.

[0644] In order to predetermine the respective application dose D.sub.1, D.sub.2, and others, in the embodiment discussed herein, data from the data storage M is used, which comprises pharmacological, pharmacodynamic, pharmacometric and/or pharmacokinetic data. The data may be models, in particular PK models, as well as PK curves. They are preferably patient-specific.

[0645] These pharmacological, pharmacodynamic, pharmacometric and/or pharmacokinetic data or models include, in the example of FIG. 4, temporal courses of concentrations of the substance S in the body of the user after the respective applied doses, referred to herein as PK curves. The curves shown reflect the temporal course of the concentration of a specific substance S resulting from the applied dose and the amount of the applied doses. The curves also reflect the processes of absorption, distribution, metabolization and elimination in the body. Such pharmacokinetics models follow statistical distributions, e.g., taking into account those with mean and standard deviation, and are mostly patient-specific, i.e., they may run differently from patient A to patient B, which is why they may also be stored in the data storage M for the different user or user collectives according to different statistical distributions. Since the course of such PK curves depends on the way of administration and the dose, the two PK curves marked with reference numerals in FIG. 4 are designated as PK50 for the intranasal administration of 50 g fentanyl on the one hand and as PK25 for the intranasal administration of 25 g fentanyl on the other.

[0646] In the example of FIG. 4, pharmacological, pharmacodynamic, pharmacometric and/or pharmacokinetic data, as they may be stored in the data storage M, optionally also include information on the substance S such as t.sub.max, which may indicate the point in time at which the highest concentration C(t) is present in the body, for example in the blood, after application of a dose D. The duration of t.sub.max may be used as a locking period, at least initially or subsequent to a first dose, in this case the initial dose D.sub.0. Likewise, the locking period may be based on t.sub.max in that the locking period is e.g. only 90% of t.sub.max, or is determined to be shorter or longer than t.sub.max by a number of minutes, etc. Likewise, values above 100% of t.sub.max are possible, e.g., 110% of t.sub.max, which is after t.sub.max, if one wishes to figure in a delay in which the administered substance passes from the blood to the site of action, or if t.sub.max is 13 minutes, but the locking period is to be set at e.g. 10 minutes for practical reasons.

[0647] The electronic control device 9 may, therefore, be programmed to read out also such data stored in the data storage M relating to the substance S and to take this into account upon predetermining the next application dose D.sub.n of substance S.

[0648] As shown schematically and exemplarily in FIG. 4, there was initially administered to the user an initial dose D.sub.0 of 50 g of intranasal fentanyl at the initial point of time tA.sub.0. The concentration floods up to a first maximum C.sub.1max, which is why the locking period end T_vain.sub.1_E of the first locking period T_vain.sub.1 is also defined for this point of time, whose locking period begin T_vain.sub.1_s is at tA.sub.0.

[0649] If only the initial dose D.sub.0 were applied to the user, the concentration C(t) would decrease over time and, assuming the PK curve PK50 shown in dashed lines in FIG. 4, would be halved after approximately 30 minutes.

[0650] However, since such a halving obviously does not meet the needs of the user who has actuated the requesting device 1 at the actuation point of time tB.sub.1, a first application dose D1 in the amount of, for example, 25 g fentanyl is administered to them at the first dispensing point of time tA.sub.1. The predetermination of this amount carried out at the predetermination point of time tV.sub.1 has shown that 25 g fentanyl is sufficient, given the course of the PK50 curve, to achieve a concentration in the interplay between decreasing effect or concentration of the initial dose D.sub.0 and simultaneously increasing effect or concentration of the first application dose D.sub.1, which, on the one hand, does not exceed the initial dose D.sub.0 of 50 g fentanyl, which was initially considered as sufficient, and, on the other hand, does not fall below a desired therapeutic effect-producing concentration C.sub.ED of about 45 g fentanyl.

[0651] The concentration C.sub.ED of about 45 g fentanyl prompting the therapeutic effect desired by the user is recognized by the control device 9 in that it recognizes that the user has obviously missed the desired therapeutic effect from the actuation point of time tB.sub.1, which is only shortly before the first dispensing point of time tA.sub.1, which has caused him to actuate the requesting device 1.

[0652] As FIG. 4 shows, the user attempts to request two further applications during the locking period T_vain.sub.1 (at the points of time tB.sub.1_v1 and tB.sub.2_v1), since the desired therapeutic effect has apparently not occurred or has not yet occurred. These applications are refused because the concentration of the initial dose D.sub.0 has not yet reached its maximum, but in any event the locking period T_vain.sub.1 has not yet ended. It will reach its maximum only towards the end of the locking period T_vain.sub.1_E. Since it can now be seen that the actuation point of time tB.sub.1 does not occur until some time after the end of the locking period T_vain.sub.1_E, the system may use the PK curve to derive a concentration at which the desired therapeutic effect occurs. In this case, an initial dose D.sub.0 of 50 g fentanyl results in a therapeutic time window of 8 minutes (from minute 7 to minute 15).

[0653] It can also be seen in FIG. 4 that the concentration for the desired therapeutic effect is already reached at minute 7. This can be seen from the fact that from this point on, no further futile actuation points of time tB.sub.mvn occur during the locking period T_vain.sub.1. As can be seen, however, the maximum concentration of the initial dose D.sub.0 has not yet reached its maximum. One can use the concentration prevailing at the last futile actuation point of time tB.sub.3_v1 for verification by matching this prevailing concentration with the expected actuation point of time after T_vain.sub.1_E.

[0654] Knowing the concentration C.sub.ED prompting the desired therapeutic effect from the first actuation point of time tB.sub.1, the control device 9 may now independently predetermine the amount of the first application dose D.sub.1. It may predetermine an amount of 25 g fentanyl, knowing that the decay of the concentration C(t) due to the initial dose D.sub.0 and the simultaneous increase of the concentration C(t) due to the first application dose D.sub.1 will lead to a second maximum C.sub.2max, which will not be above a therapeutically acceptable maximum.

[0655] Using the pharmacokinetic models (PK curves), the control device 9 may optionally calculate a time when the concentration of the dose D.sub.1 will fall below the desired therapeutic effect. In FIG. 4, this takes place after another 19 minutes or 34 minutes since tA.sub.0.

[0656] If the concentration C.sub.ED prompting the desired therapeutic effect and/or the respective next maximum C.sub.nmax is known from the above considerations, the respective next locking period may be calculated from the knowledge of the point of time at which the concentration C.sub.ED or the respective next maximum C.sub.nmax will occur or will be reached. For example, the locking period T_vain.sub.1 may be taken from the data storage M in connection with the amount of the initial dose D.sub.0. The end T_vain.sub.2_E of the following, second locking period T_vain.sub.2, may however be obtained from the knowledge of the time of C.sub.2max, both may be identical to each other. Alternatively, optionally at the time, tA.sub.1, at which the concentration C.sub.ED is achieved, the point in time at which the concentration C(t) will have dropped again to the concentration C.sub.ED may already be calculated. Half of the difference between these two points of time, as well as another part of it (e.g., 40%, 35%, etc.), may be set as the duration of the respective next locking period.

[0657] Alternative approaches are also included. In general, the calculated time for the next fall below C.sub.ED could be selected as the locking period, or shortly before. This would be the case in FIG. 4 at 58 minutes from tA.sub.0. So, the control device 9 could set the locking period to the next target concentration C.sub.ED (at minute 58 in FIG. 4) at tA.sub.2, here i.e. tV.sub.2.

[0658] The amounts of the further application doses, e.g. D.sub.2 (in this exemplary case 25 g fentanyl each) would be predetermined following similar considerations as for D.sub.1: they were determined taking into account the amount of previously administered application doses as well as the time elapsed since their application; for the second application dose D.sub.2, a residual concentration attributable to the initial dose D.sub.0 and the first application dose D.sub.1 was taken as a basis; for the third application dose, not shown here, the residual concentration attributable to the initial dose D.sub.0, the first application dose D.sub.1 and the second application dose D.sub.2 would be or have been taken as a basis. A residual dose is thereby co-determined by the amount of the respective previous application as well as the time elapsed since its application.

[0659] The amount of the next application dose D.sub.n may be predetermined such that the concentration in the body, in particular in the blood, of the user will only drop again to the target concentration C.sub.ED after a predetermined time period has elapsed, which may be adjusted e.g. by the physician or other authorized persons, beginning from the dispensing point of time tA.sub.n of the next application dose D.sub.n.

[0660] As FIG. 4 shows, the user actuates the requesting device 1 at actuation points of time tB.sub.1_v1, tB.sub.2_v1 and tB.sub.3_v1, i.e., during the locking period T_vain.sub.1. However, since these three actuations lie within the locking period T_vain.sub.1, the user cannot obtain an application dose D therewith. Nevertheless, the control device 9 records the three unsuccessful actuation attempts and their actuation points of time. In the example of FIG. 4, they are at minute 2 (tB.sub.1_v1) and at minute 4 (tB.sub.2_v1) and at minute 7 (tB.sub.3_v1), respectively, and may optionally be stored in the data storage M. If the unsuccessful actuation attempts are analyzed for this, such as the time interval between them, when they stop, etc., then, to a first but sufficient approximation, the concentration C.sub.ED which is desired by the user and which produces the intended therapeutic effect may be detected or defined.

[0661] In FIG. 4, feedback points of time tF.sub.1_1, tF.sub.1_2, tF.sub.1_3 and tF.sub.1_4 are indicated. They stand for moments in which the user actuates a feedback device 8 to indicate using feedback that they are satisfied or not satisfied with the felt effect of the respective concentration present at the time of feedback. Said user may thus signal to the nasal applicator, for example, that they are currently free of pain, that they would not prefer a higher concentration in the body, etc.

[0662] In FIG. 4, one can see in the PK50.sub.D0 curve that there is a straight line from about minute 45, i.e. the slope remains constant (pseudo-equilibrium Lambda).

[0663] The elimination half-time is now the time in which the prevailing concentration at minute 45 is halved.

[0664] According to the literature, the elimination half-time of fentanyl ranges from 3 to 12 hours, depending on habituation.

[0665] FIG. 5a shows exemplarily and schematically using three exemplary PK-curves PK50.sub.D0_+SD, PK50.sub.D0_M and PK50.sub.D0_SD the statistical distribution (mean and standard deviation) of the possible concentration courses in the user's body after administration of 50 g intranasal fentanyl, which were obtained from a sufficiently large population. There may be more than just three curves lying between the thresholds shown, i.e. the corresponding study of the collective/population may have resulted in more than just three PK curves distinguishable from each other. All of them, or the models on which they are based, may be stored in the data storage M and/or taken into account by the control device 9. For the sake of simplicity only three PK curves are shown and discussed here.

[0666] In general, equal doses of the substance may lead to different concentrations of C(t) in the body depending on the individual patient. This is influenced by various factors, such as pharmacogenetics, intraindividuality, age, weight, gender, previous medication, previous diseases, etc. Furthermore, different nasal anatomies, the nasal condition, the angle of application, how deep the nasal attachment is inserted and how the manually triggered nasal spray is operated may play a role in the course of the respective PK curve, which influences the concentration C(t) in the body over time.

[0667] By using population pharmacokinetic models such as the PK curves shown in FIG. 5a, PK50.sub.D0_+SD (mean plus one standard deviation), PK50.sub.D0_M (mean), and PK50.sub.D0_SD (mean minus one standard deviation), such differences may be mapped.

[0668] As can be seen, the same dose of 50 g intranasal fentanyl leads to three different concentration maxima C.sub.1max_SD, C.sub.1max_M and C.sub.1max_+SD for these three exemplarily selected curves. A plurality of other curves could also be displayed. They would in turn have different concentration maxima. The time until the maximum concentration does not differ in the three curves shown and also not in those not shown from the plurality of curves, or if it does, only marginally. The end T_vain.sub.1_E of the locking period T_vain.sub.1, which is oriented to the time at which the concentration maximum C.sub.1max_SD, C.sub.1max_M and C.sub.1max_+SD is reached, therefore, ends at the same time for each of the three curves of FIG. 5a.

[0669] If one assumes that the initial dose D.sub.0(D.sub.0=50 g) is applied at the point of time tA.sub.0, then the control device 9 may calculate the maximum concentrations C.sub.1max_SD, C.sub.1max_M and C.sub.1max_+SD (and many more) using the population pharmacokinetic models. However, since the time to reach these maximum concentrations is the same for all variants, the control device 9 sets the first locking period (T_vain.sub.1, see FIG. 5a) for all three PK curves equal to the time until the maximum concentration is reached, which in this case is set to 10 minutes as an example. Reaching the maximum concentration may take place in a range. In the present case of intranasal fentanyl, it is between 10 and 12.8 minutes. Since the increase in concentration in the range of 10 to 12.8 minutes is very small, one rounds the time to a practical measure such as, e.g., 10 minutes in this case. Of course, one could also choose 11, 12 or 13 minutes. Thus, if at tA.sub.0 the initial dose D.sub.0 (D.sub.0=50 g) is applied, the respectively resulting maximum concentration is calculated, the flood time until reaching the maximum concentration C.sub.1max_SD, C.sub.1max_M or C.sub.1max_+SD is calculated, the length of the locking period T_vain.sub.1 (here 10 min) is calculated and T_vain.sub.1_S and T_vain.sub.1_E are set.

[0670] According to the different courses of the three PK curves PK50.sub.D0_+SD, PK50.sub.D0_M and PK50.sub.D0_SD, one would, at the first actuation point of time tB.sub.1, at which the concentration falls below the concentration prompting the therapeutic effect desired for the user, at which the patient would receive the first application dose D.sub.1 upon request (points of time concerning actuation by the patient, predetermination etc. are not shown here for reasons of simplification or fall together with the first dispensing point of time, which may actually be the case in practice), calculate (or read off with a view to the PK curves plotted as in FIG. 5a) a different concentration C.sub.ED1_+SD, C.sub.ED1_M, C.sub.ED1_SD respectively, which respectively prompts the desired therapeutic effect. This concentration is also referred to herein as the target concentration or C.sub.ED. Its value is based, among other things, on pharmacodynamics.

[0671] It should be noted that the actuation point of time tB.sub.n may correspond to the predetermination point of time tV.sub.n and/or the dispensing point of time tA.sub.1. Thus, for example, the following may apply: tB.sub.1=tV.sub.1=tA.sub.1.

[0672] FIG. 5a shows that the concentration C.sub.ED1_+SD, C.sub.ED1_M, C.sub.ED1_SD had already been present before the dispensing point of time t.sub.A1 as C.sub.ED1_+SD, C.sub.ED1_M, C.sub.ED1_SD at 5, 6 and 8 min, respectively. This may also be derived by the omitted tB.sub._v's.

[0673] The foregoing is the basis for an embodiment discussed with reference to FIG. 5b, in which the nasal applicator 100 considers, in a specific manner, the user's actuation behavior.

[0674] If one draws a line (straight line through two points) in FIG. 5b beginning from tA.sub.0 to the corresponding concentrations C.sub.1max_SD, C.sub.1max_M und C.sub.1max_+SD, one obtains three straight lines, each with a different slope. If one now looks at the increase in concentration on the basis of the time intervals, one could already make an assessment of which curve the user might be assigned to, because the PK50.sub.D0_+SD curve has the greatest increase in concentration in the same time interval and the PK50.sub.D0_SD curve the smallest. Since the desired therapeutic effect depends on the concentration, one can make an initial assessment.

[0675] FIG. 5b schematically shows the exemplary procedure for determining, selecting and/or defining an individual PK curve PK.sub.Ind, which represents the agent concentration course of 50 g intranasal fentanyl of a concrete, individual user. It should be noted at this point that the target in determining an individual temporal concentration course, as used herein, need not always be an individual PK curve of the user. According to the present invention, it may also be sufficient if, for example, the statistical mean value curve PK50.sub.D0_M is used as an orientation, or if threshold curves such as the mean plus standard deviation curve or the mean minus standard deviation curve or others are approached and the range in which the user moves is known.

[0676] FIG. 5b encompasses the illustration of FIG. 5a, but supplements it from the first dispensing point of time tA.sub.1 with the administration of a first application dose D.sub.1 in the amount of, for example, 30 g fentanyl.

[0677] From the first dispensing point of time tA.sub.1, the PK curves PK30.sub.D1_+SD, PK30.sub.D1_M and PK30.sub.D1_SD assumed before this time are applied respectively. Based on the target concentrations C.sub.ED1_+SD, C.sub.ED1_M, C.sub.ED1_SD determined in FIG. 5b, the control device 9 or the algorithm determines a plurality of possible doses and concentrations C(t) derived therefrom, which allow an assessment/categorization, i.e. when the expected points of time of the next actuation for requesting a further application dose would have to occur. In this case, the system has defined 30 g, and the system cumulates the previous curves and, based on the determined target concentrations C.sub.ED1_+SD, C.sub.ED1_M, C.sub.ED1_SD, projects the respective curve courses into the future. It is determined at which point of time the target concentrations C.sub.ED2_+SD, C.sub.ED2_M, C.sub.ED2_SD should be mathematically undercut fall below. In the example of FIG. 5b, they are marked tB.sub.2_+SD, tB.sub.2_M and tB.sub.2_SD. Based on this check, the control device 9 may determine in which range or on which curve the user is present. The user may be better classified via these and other iterations.

[0678] Three possible cases are considered below:

[0679] Case 1: If the population pharmacokinetics curve PK30.sub.D1_M (mean value) applies to the concentration change in the user's body, the user is a good 24 minutes above the desired therapeutic effect concentration, namely from minute 18 to minute 42. Said user would not perform an actuation until minute 42 at time tB.sub.2_M, which, after a predetermination, finally leads at the application point of time tA.sub.2_M to a re-dispensing of a (second) application dose D.sub.2_M requested by them.

[0680] Case 2: If the population pharmacokinetics curve PK30.sub.D1_+SD (mean plus one standard deviation) applies to the concentration change in the user's body, the user would be 21 minutes above the desired therapeutic effect concentration, namely from minute 18 to minute 39. Said user would not make an actuation until minute 39 at the point of time tB.sub.2_+SD, which after a predetermination finally leads at the application point of time tA.sub.2_+SD to a re-dispensing of a (second) application dose D.sub.2_+SD requested by them.

[0681] Case 3: If the population pharmacokinetics curve PK30.sub.D1_SD (mean minus one standard deviation) applies to the concentration change in the user's body, the user would be a good 27 minutes above the desired therapeutic effect concentration, namely from minute 18 to minute 45. Said user would not dispense an actuation until minute 45 at point of time tB.sub.2_SD, which, after a predetermination, would eventually lead at the application point of time tA.sub.2_SD to a re-dispensing of a (second) application dose D.sub.2_SD requested by them.

[0682] On the basis of the actuation points of time tB.sub.2_+SD, tB.sub.2_M, or respectively tB.sub.2_SD, the control device 9 thus recognizes whether the user's individual PK curve is now the PK curve PK30.sub.D1_+SD, the PK curve PK30.sub.D1_M, or the PK curve PK30.sub.D1_SD (or one of the countless further PK curves which the control device 9 may also consider). If the requesting time is at tA.sub.2_+SD, the PK curve PK30.sub.D1_+SD applies. If the requesting time is at tA.sub.2_M, the PK curve PK30.sub.D1_M applies. If the requesting time is at tA.sub.2_SD, the PK curve PK30.sub.D1_SD applies.

[0683] If an initial direct association between a temporal course and the considered user is not possible, the control device 9, nevertheless, approaches the target using a process of elimination and categorizes/determines for the specific user on the basis of their actuation behavior which temporal concentration course or which curve reflects them best. After the titration phase (which is a determination phase or finding phase), which is shown in FIG. 5b and may possibly extend beyond the times shown in FIG. 5b, a categorization or classification of the user may take place. Subsequently, the amount of the following application doses may be determined and/or an individual, dose-based or concentration-based treatment plan can be set up in a time-controlled manner.

[0684] If one follows the above procedure, then it is possible, by postulating one or any number of PK curves as being possible, individual PK curves of the user, a priori or as a plurality of hypotheses (such as: the PK curve PK30.sub.D1_+SD applies to the user, or the PK curve PK30.sub.D1_M applies to the user, or the PK curve PK30.sub.D1_SD applies to the user), to generally check the correctness of the applicable or raised hypotheses already following a first initial dose or application dose D.sub.0, D.sub.1, D.sub.2, etc., or a next application dose D.sub.n. This results in an individual pharmacokinetic model for the user, which may be used as a basis for future application doses. In the example of FIG. 5b, the PK curve PK30.sub.D1_+SD is defined at the actuation point of time tB.sub.2_+SD as the PK curve PK.sub.Ind and used as the basis for the necessary calculations in future predeterminations of application doses.

[0685] A check whether the individual pharmacokinetic model determined in this way does actually apply, may optionally be carried out at any time in the course of further treatment and in connection with further application doses D.sub.n, D.sub.n+1, etc.

[0686] FIG. 6 shows a nasal applicator 100 of a further exemplary embodiment. The nasal applicator 100 is shown in FIG. 6 in a sectional illustration or in apartially indicatedpartial section.

[0687] Using the requesting device 1, the user may forward a next application dose D.sub.n of the substance S.

[0688] In the following, there will discussed those components which have not already been explained with reference to FIG. 1.

[0689] Thus, the nasal applicator 100 comprises a dispenser 3 which conducts a dosing of the application dose to be dispensed, i.e. determines the quantity. The dispenser 3 is exemplarily designed here as a loading device 15, which defines the amount of the application dose to be delivered by determining how large this amount will be, respectively. In order to segregate the desired application dose, the loading device 15 may optionally be pulled back further or less farseen from a nasal attachment 4along the double arrow, for instance automatically or by hand.

[0690] An application device 17 forhere: activelyapplying the respectively requested application dose via the connection site 4a or the nasal attachment 4 is exemplarily provided in FIG. 6 as a combination consisting of, or having, a motor, here e.g. an electric motor 19, and a spindle 21.

[0691] Electric motors, as referred to herein, may be, for example, brushless or have a brush. They may be designed, for example, as internal rotor motors, external rotor motors and/or slotless motors. An encoder may be integrated, such an encoder may be arranged externally, the same applies to a controller of the motor.

[0692] The motor, in some embodiments, may be a stepper motor such as a hybrid stepper motor, a flat motor, a hollow-shaft motor, a servo motor, an asynchronous motor, a synchronous motor, or a traveling wave motor, or the like.

[0693] In several embodiments, the motor may be controlled using open control and/or closed-loop control, and/or using an encoder and/or a controller. Encoders may be, for example, optical transmitted light encoders or reflective encoders, magnetic encoders or the like.

[0694] The motor may be or is controlled via the current consumption. If for example the motor approaches or moves to an end position (up or down), the current consumption of the motor increases e.g. from 0.5 A to 1 A. This means that an end position or stop has been reached. This measurement value may, therefore, also be used to control the motor, i.e. to signal (to it) when e.g. it should switch off.

[0695] In order to control the nasal applicator or its motor, a displacement sensor, a flow sensor, limit switch (microswitch) may optionally be used. Additionally or alternatively, a timed control (e.g. energization for a predetermined time period) is also encompassed by the present invention.

[0696] The motor, or the spindle combination, may in certain embodiments comprise a brake, e.g. a magnetic brake, eddy current, spring pressure brake, a limit switch at top and/or bottom dead center or limit point of the stroke, etc.

[0697] The motor or motor-spindle combination may alternatively or additionally include a damper to eliminate or improve, e.g., resonance and noise problems.

[0698] The nasal applicator 100 of FIG. 6 optionally comprises a dose chamber 13 distinguishable from the substance reservoir R. It serves to receive the application dose of the substance S stored in the substance reservoir R, for which in particular any embodiment disclosed herein may be provided, in order to subsequently dispense it.

[0699] In order to be able to dispense the application dose, the dose chamber 13 must first be filled with it. In the embodiment of FIG. 6, this task is performed by the loading device 15.

[0700] The dose chamber 13 may be actuated to execute a sequence of a suction stroke and a dispensing stroke, as described below.

[0701] Deaeration of the system works identically, except that air is a compressible medium and substance S is a non-compressible medium. When or by deaerating, the system will travel the full stroke path and may optionally aim for different parameter values for speed, force, pressure and/or acceleration of or for deaeration as after deaeration, and in particular for the delivery of the substance S.

[0702] When the loading device 15 and/or the application device 17 is moved away from the upper dead center/end point/beginning point/initial point (on the side of the one-way valve 23b) with respect to the orientation in FIG. 6, a negative pressure is created in the dose chamber 13. This negative pressure allows substance S to flow out of the substance reservoir R into the dose chamber 13. The plug 17a in the substance reservoir R is also trailed by this negative pressure and thus a collapsible container is created (suction stroke). In this, the one-way valve 23b closes, and the one-way valve 23a opens. This may be done mechanically, pneumatically, hydraulically, electrically, etc.

[0703] As an alternative to controlling the valves 23a, 23b by negative pressure, the valves 23a, 23b may be controlled electrically. For this purpose, the position of the loading device 15 is reverted to.

[0704] The valves 23a, 23b may also be designed or operated in any combination of the aforementioned modes of operation.

[0705] In order to apply the substance S (dispensing stroke) out of the dose chamber 13, the direction of the loading device 15 is reversed, and it thereby becomes the application device 17, which travels with a predetermined speed, force, pressure, acceleration in the direction towards the one-way valve 23b. When the path is reversed, a positive pressure is created in the dose chamber 13, which closes the one-way valve 23a and opens the one-way valve 23b. This allows the substance S to be forced through the nasal attachment 4 via the connection site 4a. The valve control may be as described above.

[0706] Optionally, different values for speed, force, pressure and/or acceleration are applied or aimed for in the suction stroke than in the dispensing stroke.

[0707] The dose chamber 13 may be manufactured with high precision to provoke minimal variability in the delivery quantity, which may also apply to the loading device 15 and the application device 17.

[0708] This can be achieved by using a plastic with low shrinkage or low water absorption. Alternatively or additionally, e.g. in FIG. 6, a sleeve may be pressed-in which preferably has very close tolerances in diameter. This allows better control of the application volume. The application volume is given by the formula:

volume=area*stroke. The area is that of a circle A=d.sup.2*/4.

[0709] Plastics with low shrinkage or low water absorption can be called dimensionally stable plastics.

[0710] Dimensional stability refers to the ability of polymers to maintain their size under various environmental conditions. A dimensionally stable plastic, therefore, tends less to moisture absorption and displays less thermal expansion.

[0711] Dimensional stable plastics include polymers such as PEEK, PPS, PSU, PPSU, PEI and PET.

[0712] Moisture absorption may lead not only to a change in size, but also to a change in material properties. This may have an effect on, among others, the mechanical strength and/or electrical properties, such as electrical conductivity and the dielectric loss factor.

[0713] A polymer without water absorption is, for example, PTFE. The following polymers are plastics with very low water absorption: PEEK, PPS, PSU, PPSU, PEI, PVDF, PET, PPE, PP and PE. Low water absorption is also recorded for POM, PA12, PC and ABS.

[0714] The dose chamber 13, the application device 17, and/or the loading device 15 may be self-sealing and/or comprise a seal such as a sealing ring 16, piston rings, O-rings, sealing lips, etc.

[0715] The dose chamber 13, and/or any elements that come into contact with the substance such as the application device 17, the loading device 15 and/or others, may be coated. A possible coating may be e.g. parylene, and/or may be of inert materials such as glass, and/or may be of technical plastics such as cycloolefin copolymers (COC), cyclo-olefin polymers (COP), etc.

[0716] Here, as in any other embodiments, the dose chamber 13, the application device 17, and/or the loading device 15 may consist of or comprise materials that do not require lubrication, e.g., POM homopolymer, Teflon, etc. Lubricants, like e.g. silicone oil, may also be used, or coatings with which friction is reduced. In some embodiments, additives may also be added to the plastics to improve sliding properties such as, e.g., CORDULEN, montan wax, high molecular weight polyethylene wax (PE-LD, PE-HD), fluoroelastomers, etc.

[0717] In certain embodiments, the dose chamber 13, the application device 17, and/or the loading device 15 may consist of or comprise other materials such as plastic.

[0718] As can be seen from the foregoing explanations, the dose chamber 13 is variable in that the loading device 15 separates sometimes more and sometimes less amount of substance S from the substance reservoir R, wherein the space in which the thus separated application dose is present before it is delivered may be defined as the dose chamber 13.

[0719] The substance reservoir R may be or will be clamped, rotated, inserted, fixed in a guide or may be or will be guided in the housing.

[0720] The substance reservoir R may be connected to the loading device 15, the application device 17, the nasal attachment 4, the dispenser 3, or the connection site 4a. The connection may be established by a flexible or rigid line 22. The line 22 may be stationary, or may be movable with the application device 17 and/or the loading device 15.

[0721] The substance reservoir R may be connected to the dose chamber 13 by, e.g., a Luer lock, pin, needle, spike with or without a vent, etc.

[0722] To establish a fluid connection between the dose chamber 13 and the substance reservoir R, e.g. a needle 38 may be provided, which pierces e.g. a septum 39 of the vial.

[0723] A filter, e.g. a (e.g. 22 m) particle filter or a porous membrane (e.g. a Porexfilter), may be interposed. In some embodiments, this filter may be disposed at the outlet of the dose chamber 13, and a second filter may additionally be provided there.

[0724] As will become clear from the following elaborations, the loading device 15 may be identical to the application device 17, but it may also be provided separately therefrom.

[0725] Although the application device 17 and/or the loading device 15 may have an energy storage for mechanical energy or spring energy and/or hydraulic and pneumatic energy as an energy application mechanism, this is not the case in the embodiment of FIG. 6.

[0726] The electrical energy storage 20 may be integrated in the application device 17 and/or the loading device 15 or connected to them by an external connection.

[0727] The integrated energy storage 20 may be charged for a release and may be charged after each application by a charging device, e.g. a Qi charging pad, or in a cradle by a PIN connection.

[0728] The electrical energy storage device 20 may be a capacitor or the like.

[0729] Power may be supplied via power cable, power supply, etc., or via Ethernet (LAN), Power over Ethernet (PoE). The latter refers to a method of supplying power to network-enabled devices via the eight-wire Ethernet cable. Such a supply may be provided herein. In some embodiments, solar cells or mechanisms for energy harvesting may alternatively be provided for this purpose.

[0730] In FIG. 6, the application device 17 and/or the loading device 15 are designed as an electric drive, herein with electric motor 19 having a spindle 21, which are coupled.

[0731] In other embodiments, this coupling may also take place via a transmission or be designed with a transmission.

[0732] With reference to FIG. 6, it should be noted that in several embodiments, such as that of FIG. 6, the application device 17 and the loading device 15 may be implemented or realized by a common mechanism, wherein the mechanism, for example, when it travels in a first direction (for example away from the connection site 4a), fills the dose chamber 13 as the loading device 15, and when it travels in a second direction, which may be opposite to the first (for example towards the connection site 4a), discharges the contents of the dose chamber 13 as the application device 17, for example, via the nasal piece. A counter-rotation of spindle 21 and/or motor 19 during suction on the one hand and application on the other hand may be provided, as has already been described elsewhere herein. Alternatively, rotation in the same direction is possible for both filling and emptying the dose chamber 13, as explained above, for example, with reference to the crankshaft gear. Likewise, filling and emptying are possible with mutual rotation when the crankshaft gear is used, as described above.

[0733] The application device 17 and/or the loading device 15 are releasably or non-releasably connected to the spindle 21 and/or the motor 19.

[0734] The substance reservoir R, the application device 17 and/or the loading device 15 may be designed as disposables.

[0735] The application device 17, the loading device 15 may be designed as a reusable product.

[0736] Both optionally provided housing shells may be designed as disposables.

[0737] The electronic control device 9, motor 19, spindle 21, and/or other components may be reusable.

[0738] The nasal applicator 100 of FIG. 6 further comprises an optional mechanism for changing the capacity volume of the dose chamber 13. By or with this mechanism, the capacity volume of the dose chamber 13 may be varied in order to have or receive a partial amount of the substance S, making it possible to apply application doses of different sizes.

[0739] In some embodiments, this mechanism is part of the dispenser 3, but in others such as the present one, it is not.

[0740] The electronic control device 9, see FIG. 1, if provided, may be programmed to move and/or cause the application device 17 to apply at a variety of speeds, forces, pressures, accelerations, flow rates.

[0741] A motor-driven, nasal device may be used to solve the problem of each user applying a different speed, force, pressure, acceleration when releasing manually through pressing. It is not guaranteed that each user will generate the same speed, e.g. release speed or ideal release speed. Since the release speed has the greatest influence on the droplet size distribution, the spray pattern and the plume geometry, a release that is always identical between users is of particular advantage, since this always ensures a consistent spray pattern, in particular the droplet size distribution, the spray pattern and the plume geometry and application volume, compared to a manual release.

[0742] In this way, it can be advantageously ensured that when the next application dose is applied, the stroke path required for this, i.e. the complete stroke distance, is always covered. If e.g. for a 150 L dose, a distance of 5 mm has to be covered, then it can be ensured as described herein that not only e.g. 4 mm are covered, which could be possible with a manual solution based on the pressure strength or pressure depth, but, due to the options described herein, always the complete required stroke path is covered.

[0743] Additionally or alternatively, the electronic control device 9 may be programmed in order to act on the mechanism for changing the capacity volume of the dose chamber 13. This may also be done manually and the release may still be automatic.

[0744] The droplet size distribution, the spray pattern, the plume geometry may preferably be adjusted, and optionally adjusted differently for each application amount.

[0745] Depending on the agent and its properties, such as, e.g., viscosity, surface tension, etc., a different speed, a different force, a different pressure, a different acceleration, a different flow rate may be required. The device may, in some embodiments, run at a separate speed, force, acceleration, flow rate, or pressure for each dose amount. This is set or may be set, for example, in advance.

[0746] In certain embodiments, a sensor may detect the position or release position, e.g. vertical or horizontal (and everything in between), and then adjust the speed, force, pressure, acceleration to that position, respectively.

[0747] In the embodiment of FIG. 6, the loading device 15 for loading the dose chamber 13 with the application dose of substance S, comprises at least one first one-way valve 23a or check valve and/or the dose chamber 13 is (de)limited by at least one first one-way valve 23a or check valve. This valve may be arranged, e.g., in a piston itself or at any position, e.g. at any position in the inlet line from the substance reservoir R to the dose chamber 13.

[0748] In the embodiment of FIG. 6, the loading device 15 comprises at least one second one-way valve 23b or check valve.

[0749] Alternatively, e.g., the first valve 23a is designed as a switchable three-way valve and/or designed differently. Thus, the first valve 23a may also perform the function of two valves as a singular element.

[0750] In this, the dose chamber 13 is exemplarily limited by at least the second one-way valve 23b or check valve.

[0751] Optionally, the second check valve 23b comprises relative to the dose chamber 13 an opening direction opposite to that of the first check valve 23a.

[0752] Optionally, the function of the first one-way valve 23a and the function of the second one-way valve 23b may be combined into a common component, like e.g. a valve element.

[0753] The dose chamber 13 may optionally be in communication with, or brought into communication with, the atmosphere via a deaeration valve, not shown herein. It may be provided to use such a deaeration valve to operate the initial deaeration of the system and/or to eliminate air bubbles at a later time. A filter may be provided at a suitable position.

[0754] The device optionally comprises two housing parts, namely an upper housing part 2b and a lower housing part 2c, which are separated by a housing splitline 2d in FIG. 6.

[0755] In the schematic representation of FIG. 6, the housing upper part 2b contains the substance reservoir R, the dose chamber 13, the application device 17 and/or the loading device 15. Valves, filters, deaeration, the connection site 4a for the nasal attachment 4, etc. may also be provided in the housing upper part 2b.

[0756] The housing lower part 2c comprises the electronic control device 9, the motor 19, the spindle 21, the optional encoder, the controller, the brake, the damper, the energy storage 20, the requesting device 1, etc.

[0757] Components mentioned above are arranged only exemplarily as shown in FIG. 6. They may be arranged in any combination.

[0758] One or both of the housing shells or housing parts 2b, 2c may be disposables. The nasal applicator 100 may be present completely assembled, sterilized, packaged or may be shipped or delivered completely assembled, sterilized, packaged. Alternatively, it is first completed (or assembled) on site, at the patient's bedside, by the patient, by the physician, etc. For example, the substance reservoir R may still have to be inserted into the housing upper shell and the latter then assembled with the housing lower shell.

[0759] The electronic control device 9, the motor 19, the spindle 21, the optional encoder, the controller, the brake, the damper, the energy storage 20 and/or the requesting device 1, may, in any combination with each other, form a unit. They can be, or are, inserted into a housing lower part 2c, which then forms the housing 2 together with the housing upper part 2b. Optionally, upon disassembly, the housing shells (upper and lower parts) 2b, 2c could be opened and disposed of. The electronics may be removed, without being touched, from the lower shell or housing lower part 2c.

[0760] The housing parts 2b, 2c, alone or together, may for example also be intentionally destroyed after completion of the user's treatment in order to prevent further use of the nasal applicator. To this end, it may be provided to break off e.g. an optional snap hook or to irreversibly damage, break off, displace, etc. another form-fit connection. For example, one deforms the snap hook, displaces a connecting member or lock, etc.

[0761] The nasal applicator 100 may be automatically and/or manually emptied after treatment and discarded as a whole. Alternatively, it may be disassembled into parts and only partially discarded or reprocessed or reused, in particular, for example, the electronic control device 9, the motor 19, the spindle 21, etc. are suitable for this purpose.

[0762] The nasal applicator 100 may comprise a lid which may be opened for inserting the substance reservoir R and/or the electronic control device 9.

[0763] A sealing ring 16 may be provided to ensure tightness between the loading device 15 and/or application device 17, on the one hand, and the surrounding sleeve or shaft, on the other hand.

[0764] A flow sensor 11a may be provided. It may be part of or constitute or represent the detection device.

[0765] An optional plug 17a is provided to limit the volume of the substance reservoir R, it may be arranged in a shiftable manner.

[0766] An optional spring may be provided in this, or any other, embodiment, which presses directly or indirectly against the plug 17a to move it, upon release of the nasal applicator 100, out of a position it may have assumed over an extended time period due to storage reasons.

[0767] The valve 23a shown in FIG. 6, may in any embodiment be disposed optionally, at, on, and/or within the application device 17 and/or the loading device 15 or in close proximity thereto.

[0768] Optionally, the line 22 through which the substance S is delivered to the dose chamber 13 may in arbitrary embodiments extend through the loading device 15 and/or the application device 17.

[0769] Optionally, the loading device 15 and/or the application device 17, may in arbitrary embodiments have a connection for the line 22.

[0770] Optionally, the loading device 15 and/or the application device 17, may in arbitrary embodiments be hollow or unobstructed.

[0771] Optionally, the line 22, may in arbitrary embodiments move together with the loading device 15 and/or together with the application device 17. In some other embodiments, the line 22 does not move with the loading device 15 and/or the application device 17.

[0772] Optionally, the substance reservoir R may in arbitrary embodiments be installed to be rotated 180 degrees relative to the embodiment of FIG. 6.

[0773] Optionally, all components may be positioned as desired in arbitrary embodiments to avoid blind installation, i.e. installation without visibility, reduce the risk of injury from needle 38, and that the substance reservoir R, which may comprise the septum 39 or other connection, can be more easily installed.

LIST OF REFERENCE NUMERALS

[0774] 100 nasal applicator [0775] 101 peripheral device [0776] 1 requesting device [0777] 2 housing [0778] 2b upper housing part [0779] 2c lower housing part [0780] 2d housing splitline [0781] 3 dispenser [0782] 4 nasal attachment [0783] 4a connection site [0784] locking device [0785] 7 dose-detection device [0786] 8 feedback device [0787] 9 electronic control device [0788] 11 detection device [0789] 11a flow sensor [0790] 12 display [0791] 13 dose chamber [0792] 15 loading device [0793] 16 seal or sealing ring [0794] 17 application device [0795] 17a plug [0796] 19 electric motor [0797] 20 energy storage [0798] 21 spindle [0799] 22 line [0800] 23a first one-way valve, check valve [0801] 23b second one-way valve, check valve [0802] 38 needle [0803] 39 septum [0804] C.sub.ED1 target concentration, concentration required for the desired effect/impact at actuation point of time tB.sub.1 [0805] C.sub.ED2 target concentration, concentration required for the desired effect/impact at actuation point of time tB.sub.2 [0806] C.sub.ED3 target concentration, concentration required for the desired effect/impact at actuation point of time tB.sub.3 [0807] C.sub.ED1_+SD first set target concentration, concentration required for the desired effect/impact on the PK curve PK50.sub.D0_+SD at actuation point of time tB.sub.1 [0808] C.sub.ED1_M first set target concentration, concentration required for the desired effect/impact on the PK curve PK50.sub.D0_M at actuation point of time tB.sub.1 [0809] C.sub.ED1_SD first set target concentration, concentration required for the desired effect/impact on the PK curve PK50.sub.D0_SD at actuation point of time tB.sub.1 [0810] C.sub.ED2_+SD second set or first estimated target concentration, concentration required for the desired effect/impact on the PK curve PK30.sub.D1_+SD at actuation point of time tB.sub.2 [0811] C.sub.ED2_M second set or first estimated target concentration, concentration required for the desired effect/impact on the PK curve PK30.sub.D1_M at actuation point of time tB.sub.2 [0812] C.sub.ED2_SD second set or first estimated target concentration, concentration required for the desired effect/impact on the PK curve PK30.sub.D1_SD at actuation point of time tB.sub.2 [0813] C.sub.ED1 first target concentration determined before the dispensing point of time tB.sub.1, concentration required for the desired effect/impact on the PK curve PK50.sub.D0 [0814] C.sub.ED1_+SD first target concentration determined before the dispensing point of time tB.sub.1, concentration required for the desired effect/impact on the PK curve PK50.sub.D0_+SD [0815] C.sub.ED1_M first target concentration determined before the dispensing point of time tB.sub.1, concentration required for the desired effect/impact on the PK curve PK50.sub.D0_M [0816] C.sub.ED1_SD first target concentration determined before the dispensing point of time tB.sub.1, concentration required for the desired effect/impact on the PK curve PK50.sub.D0_SD [0817] C(t) concentration at point of time t [0818] C.sub.nmax concentration maximum [0819] C.sub.1max first maximum on the PK curve PK50.sub.D0 [0820] C.sub.2max second maximum on the PK curve PK25.sub.D1 [0821] C.sub.3max third maximum on the PK curve PK25.sub.D2 [0822] C.sub.1max_+SD first concentration maximum on the PK curve PK50.sub.D0_+SD [0823] C.sub.1max_M first concentration maximum on the PK curve PK50.sub.D0_M [0824] C.sub.1max_SD first concentration maximum on the PK curve PK50.sub.D0_SD [0825] C.sub.2max_+SD second concentration maximum on the PK curve PK30.sub.D1_+SD [0826] C.sub.2max_M second concentration maximum on the PK curve PK30.sub.D1_M [0827] C.sub.2max_SD second concentration maximum on the PK curve PK30.sub.D1_SD [0828] D dose [0829] D.sub.0 initial dose [0830] D.sub.1 first application dose, preceding application dose [0831] D.sub.2 second application dose, subsequent application dose [0832] D.sub.3 third application dose [0833] D.sub.n1 the application dose preceding the next application dose [0834] D.sub.n next application dose [0835] D.sub.n+1 the application dose following the next application dose or the one after the next dose [0836] M data storage [0837] PK25 PK curve for 25 g fentanyl single dose [0838] PK50 PK curve for 50 g fentanyl single dose [0839] PK25.sub.Dn PK curve for 25 g fentanyl multiple dose [0840] PK50.sub.Dn PK curve for 50 g fentanyl multiple dose [0841] PK50.sub.+SD PK curve for 50 g fentanyl single dose, mean value over all considered individuals of the collective plus one standard deviation [0842] PK50.sub.M PK curve for 50 g fentanyl single dose, mean value over all considered individuals of the collective [0843] PK50.sub.SD PK curve for 50 g fentanyl single dose, mean value over all considered individuals of the collective minus one standard deviation [0844] PK50.sub.Dn_+SD PK curve for 50 g fentanyl multiple dose, mean value over all considered individuals of the collective plus one standard deviation [0845] PK50.sub.Dn_M PK curve for 50 g fentanyl multiple dose, mean value over all considered individuals of the collective [0846] PK50.sub.Dn_SD PK curve for 50 g fentanyl multiple dose, mean value over all considered individuals of the collective minus one standard deviation [0847] PK30.sub.Dn_+SD PK curve for 30 g fentanyl multiple dose, mean value over all considered individuals of the collective plus one standard deviation [0848] PK30.sub.Dn_M PK curve for 30 g fentanyl multiple dose, mean value over all considered individuals of the collective [0849] PK30.sub.Dn_SD PK curve for 30 g fentanyl multiple dose, mean value over all individuals considered in the collective minus one standard deviation [0850] PK.sub.Ind individual PK curve [0851] R substance reservoir [0852] S medical substance [0853] T_vain.sub.n locking periods [0854] T_vain.sub.n_S locking period begin [0855] T_vain.sub.n_E locking period end [0856] tA.sub.0 initial or beginning time; dispensing point of time of the initial dose; initial or beginning dose [0857] tA.sub.1, . . . , tA.sub.n, tA.sub.n+1 dispensing point of time 1 to n+1 [0858] tA.sub.2_+SD mean value of dispensing point of time over all considered individuals of the collective plus one standard deviation [0859] tA.sub.2_M mean value of dispensing point of time over all considered individuals of the collective [0860] tA.sub.2_SD mean value of dispensing point of time over all considered individuals of the collective minus one standard deviation [0861] tB.sub.1, . . . , tB.sub.n, tB.sub.n+1 actuation point of time 1 to n+1 tB.sub.2_+SD, tB.sub.2_M, tB.sub.2_SD calculated target concentration time [0862] tB.sub.1_v1, tB.sub.2_v1 futile actuation points of time during the locking period T_vain.sub.1 [0863] tB.sub.1_v2, tB.sub.2_v2 futile actuation points of time during the locking period T_vain.sub.2 [0864] tB.sub.m_vn futile actuation points of time during the locking period T_vain.sub.n [0865] tF.sub.n_1 first feedback points of time [0866] tF.sub.n_2, tF.sub.n_3 feedback points of time [0867] tF.sub.n_4 last feedback point of time [0868] tV.sub.1, . . . , tV.sub.n, tV.sub.n+1 predetermination point of time 1 to n+1