Method and apparatus for controlling temperature of drug foil substrate to generate aerosols

Abstract

A method of controlling the temperature of a drug foil substrate is disclosed, characterized in that heating is stopped while the temperature thereof is measured to determine the amount of time to subsequently heat the drug foil substrate. The method includes electrically heating a drug foil substrate coated with a solid drug film and placing it in a disposable cartridge adapted to be connected to a handheld controller. The heating method generates condensed aerosol according to a first temperature and time relation curve.

Description

Technical Field

[0001] The method and device belong to the field of temperature control of drug aerosol generation. Background Art

[0002] A sensor and a circuit for detecting the temperature of a heating element are described in CN1548934 A. During the measurement, the heating is stopped and the temperature of the heating element is allowed to stabilize for a suitable period of time.

[0003] In WO03037412A2, a method for controlling the temperature profile of a resistive element for vaporizing a drug is disclosed. The method comprises pulse heating, wherein a first high duty cycle is used for ramping up and a reduced duty cycle is used for maintaining the temperature. The time of temperature measurement is not specified. The device produces a cold central region and a hot region surrounding the center.

[0004] In WO07076688A1 a method of controlling the temperature of a heating element is described, wherein the resistance varies monotonically with temperature and the temperature is sensed after heating has ceased.

[0005] A method of maintaining the temperature of an aerosol generating device by providing current pulses (duty cycle) is described in WO14040988A2. The method comprises determining the temperature of a heating element by determining the resistance of the heating element and reducing the duty cycle by adjusting the current (e.g. by limiting the applied voltage) when the temperature is closer to a target temperature. The aerosol-forming substrate is based on tobacco.

[0006] In US2021219386 AA and US2021145074, a device is described comprising two switches; a first switch is used to interrupt the flow of current heating a resistive heating element which causes the vaporization of a vaporizable material; a second switch is used to add a reference resistor in series with the resistive heating element. The device allows the resistance of the resistive heating element to be determined and the power supplied to the resistive heating element to be controlled according to the determined resistance by regulating the flow of current.

[0007] In WO2015192084A1, an electronic evaporator is described, which includes a heating element to heat a fluid to produce steam. The evaporator includes a power control unit configured to adjust the electrical power provided to the heating element. The adjustment is based at least in part on the heating element temperature and the temperature setting to avoid the heating element exceeding its temperature setting. The heating element temperature can be measured using its resistance based on a known resistance temperature coefficient characteristic associated with the heating element, and the temperature can be determined every 100ms. In different embodiments, the evaporator includes a machine-readable medium in which a temperature coefficient resistor is stored. The main purpose of the evaporator is to avoid overheating of the steam and keep the temperature near the boiling point of the fluid. An electronic evaporator is described, which includes a heating element to heat a fluid to produce steam. The evaporator includes a power control unit configured to adjust the electrical power provided to the heating element. The adjustment is based at least in part on the heating element temperature and the temperature setting to avoid the heating element exceeding its temperature setting. The heating element temperature can be measured using its resistance based on a known resistance temperature coefficient characteristic associated with the heating element, and the temperature can be determined every 100ms. In different embodiments, the evaporator includes a machine-readable medium in which a temperature coefficient resistor is stored. The main purpose of the evaporator is to avoid superheating of the vapor and to keep the temperature near the boiling point of the fluid.

[0008] In WO2019152873, a disposable cartridge is described in which the drug is coated on an electrically heated drug foil substrate. The disposable cartridge can be connected to a handheld controller that includes electronic equipment and electrical components, including a power supply. The drug foil substrate is heated to a target temperature in an increasing manner and then a heating rate is applied. The heating rate is selected between platform heating, regulated cooling and progressive heating. However, the document does not describe how to accurately control the temperature during the heating process and the heating rate, resulting in a high dispersion of the emitted dose.

[0009] Aerosol generation from heating of the drug foil substrate may be affected by the battery voltage, which may vary depending on charge level and may also vary during any given heating cycle if high currents are applied.

[0010] The current output of the battery also affects the generation of aerosols from the heated drug foil substrate, and when high currents are applied, the current output of the battery may vary during any given heating cycle depending on its charge level.

[0011] Furthermore, depending on the ambient temperature, the heat dissipation from the drug foil substrate may vary from one inhalation to another, or even during a single inhalation.

[0012] Not only that, the evaporation of the drug from the foil substrate absorbs energy (called the enthalpy of evaporation), and this additional energy needs to be added at a precise moment, which is unpredictable, and cannot be added at another moment.

[0013] In addition, on the one hand, if the heating duration is too short, the drug foil substrate may not stay at the temperature required for drug evaporation long enough, and the emission dose will be lower than the dose required for treatment; if the heating duration is too long, the drug foil substrate may stay at the temperature required for drug evaporation longer, and the emission dose will be higher than the dose required for treatment and may contain more impurities.

[0014] In addition, on the other hand, if the drug foil substrate is overheated, the generated aerosol may contain more impurities and the emitted dose may be higher than the dose required for treatment; on the other hand, if the drug foil substrate is overheated, the emitted dose may be lower than the dose required for treatment.

[0015] In condensation aerosol delivery systems, the aerosol quality of some drugs is very sensitive to the temperature used to vaporize the drug (see, e.g., Comparative Examples 1 and Figure 1G ). The temperature heating profile (rate of temperature rise, peak temperature, and dwell time at peak temperature) will all affect the amount of drug evaporated and the purity of the aerosol. If the peak temperature is too high and / or the dwell time is too long, the aerosol purity may be negatively affected. If the peak temperature is too low and / or the dwell time is too short, the amount of drug evaporated may be too low.

[0016] In the prior art, electrical heating is mainly used in the field of electronic cigarettes to heat tobacco, herbal derivatives or liquid preparations. Temperature control in this field is very important to provide the right particle size and aerosol dosage, but in the field of drug administration, it is even more important to accurately control these parameters in order to administer a precise and reproducible dose of the drug to achieve a therapeutic effect without any adverse side effects. In addition, the purity of the administered drug is also crucial in the field of drug administration.

[0017] Therefore, there is a need for a method and apparatus that can accurately control the heating profile of a drug foil substrate so that it is at a desired temperature at every moment of the heating profile. Summary of the invention

[0018] In a first aspect, a method is disclosed for electrically heating a drug foil substrate (205) coated with a solid drug film (207) disposed in a disposable cartridge (200) according to a first temperature-time relationship curve (TP1) to generate a condensation aerosol; the disposable cartridge (200) is suitable for connection to a handheld controller (100);

[0019] TP1 includes:

[0020] heating function, whose average slope HSTP1 ranges from 1 to 5 °C / ms;

[0021] The target temperature tTTP1 ranges from 200 to 550°C, and / or

[0022] Heating time HtTP1, which ranges from 40 to 550 ms;

[0023] The method comprises:

[0024] The adjustment phase includes:

[0025] During t_heat1, a current ITP1 is applied to the drug foil substrate (205), and during t_wait1, no current is applied.

[0026] No current is applied during t_wait1, and a current ITP1 is applied to the drug foil substrate (205) during t_heat1, or

[0027] The aforementioned t_wait1 and t_heat1 are distributed in alternating sections;

[0028] Determining the temperature (T_meas) of the drug foil substrate (205) during a period t_meas1 using a temperature sensor;

[0029] If T_meas ≤ T_exp, then

[0030] t_heat1 = 1% to 100% of (t_period1 - t_meas1), and t_wait1 = t_period1 - t_meas1 - t_heat1, otherwise

[0031] t_heat1 = 0% to 100% of (t_period1 - t_meas1), and t_wait1 = t_period1 - t_meas1 - t_heat1, where T_exp is based on TP1; and

[0032] Repeat steps a) to d) to match TP1 until tTTP1 is reached and / or HtTP1 ​​has passed;

[0033] in:

[0034] The control cycle time t_period1 ranges from 0.5 to 5 ms.

[0035] The measurement time t_meas1 ranges from 1% to 40% of t_period1,

[0036] T_exp is based on the expected temperature of TP1 at any given point in time,

[0037] t_period1=t_heat1+t_wait1+t_meas1,

[0038] t_period1 is the length of time for each cycle of measuring temperature and optionally heating the drug foil substrate (205),

[0039] t_heat1 is the time for heating the drug foil substrate (205) within each t_period1,

[0040] t_wait1 is the time during which the drug foil substrate (205) is not heated within each t_period1,

[0041] t_meas1 is the time at which the temperature of the drug foil substrate (205) is measured within each t_period1, and

[0042] The current ITP1 is 30 to 400A.

[0043] The second aspect is a disposable cartridge (200) configured to perform the method of the first aspect and adapted to be connected to a handheld controller (100) of the third aspect, the disposable cartridge (200) comprising:

[0044] an air inlet (220) located at one end of the airway (203);

[0045] an air outlet (202) located at the other end of the airway (203), which is configured as a suction nozzle;

[0046] a drug foil substrate (205) with a water-impermeable surface, with or without perforations, placed within the airway (203);

[0047] a drug foil substrate support (204);

[0048] a solid drug film (207) coated on the drug foil substrate (205); and

[0049] An electrical connection (302) and / or a data connection (301) between the disposable cartridge (200) and the handheld controller (100) of the third aspect.

[0050] A third aspect is a handheld controller (100) configured to perform the method of the first aspect and adapted to be connected to a disposable cartridge (200) of the second aspect, comprising:

[0051] At least one battery (101)

[0052] at least one microcontroller (102); and

[0053] An electrical connection (302) and / or a data connection (301) between at least one battery (101), at least one microcontroller (102) and the disposable cartridge (200) of the second aspect.

[0054] The fourth aspect is a medicament comprising a drug selected from the group consisting of loxapine, alprazolam, estazolam, fentanyl, zaleplon, amoclaxan, apomorphine, pergolide, ropinirole, pramipexole, granisetron, ondansetron, palonosetron, nicotine, nicotine meta-salicylate, rotigotine, or a pharmaceutically acceptable salt thereof, the medicament being used in the method of the first aspect, the handheld controller (100) of the third aspect, or the disposable cartridge (200) of the second aspect.

[0055] The fifth aspect is a drug for a condition or episode, which is deposited on the drug foil substrate (205) of the method of the first aspect, the handheld controller (100) of the third aspect, or the disposable cartridge (200) of the second aspect, wherein when the drug is:

[0056] Loxapine or a pharmaceutically acceptable salt thereof, wherein the condition or episode is agitation, including:

[0057] Rapid control of mild to moderate agitation in adults with schizophrenia or bipolar disorder, or

[0058] acute agitation associated with schizophrenia or bipolar disorder;

[0059] alprazolam, estazolam, or a pharmaceutically acceptable salt thereof, wherein the condition or seizure is epilepsy, wherein epilepsy comprises seizures;

[0060] Fentanyl or a pharmaceutically acceptable salt thereof, wherein the condition or onset is breakthrough pain;

[0061] Zaleplon, amorant or a pharmaceutically acceptable salt thereof, wherein the condition or episode is a sleep disorder, including:

[0062] Waking up in the middle of the night, or

[0063] Insomnia in the middle of the night;

[0064] Apomorphine, pergolide, ropinirole, pramipexole or a pharmaceutically acceptable salt thereof, wherein the condition or attack is Parkinson's disease, non-attack period of Parkinson's disease and / or idiopathic Parkinson's disease;

[0065] Granisetron, ondansetron, palonosetron or a pharmaceutically acceptable salt thereof, wherein the condition or episode is:

[0066] nausea,

[0067] vomiting, or

[0068] Cyclic vomiting syndrome;

[0069] Nicotine or a pharmaceutically acceptable salt thereof, including nicotine meta-salicylate, wherein the condition or episode is nicotine addiction and / or smoking cessation; or

[0070] Ropinirole, pramipexole, or rotigotine, and the condition or episode is restless legs syndrome.

[0071] definition

[0072] As used herein, the following terms are used and have the following meanings.

[0073] i) "Disposable cartridge" means a single-dose or multi-dose cartridge comprising a drug coated on a drug foil substrate, an air inlet that may or may not be connected to a handheld controller, an airway (203), an air outlet configured as a mouthpiece, and a connector for electrically connecting it to a handheld controller (100). The disposable cartridge is connected to the handheld controller for operation.

[0074] ii) A "hand-held controller" is a reusable device comprising at least one battery, connectors, electrical parts and electronics suitable for heating the drug foil substrate after attaching a disposable cartridge to the drug foil substrate.

[0075] iii) "Electrical connection" is the means of transferring electrical power from the battery to the drug foil substrate, microcontroller or memory.

[0076] iv) "Data connection" means the means for transferring data between the microcontroller and any sensor, detector or memory, where the sensor or detector and memory are located in the disposable cartridge and / or handheld controller.

[0077] v) "Battery" means a device that stores energy in a compound capable of producing an electric current. It may be a rechargeable battery, such as a nickel-metal hydride battery, a lithium polymer battery, etc. (see WO2019152873 for more details on rechargeable batteries); or a disposable battery, such as a dry cell, an alkaline battery, a silver battery, a zinc-air battery, a lithium battery, a nickel oxyhydroxide battery, etc. When the heating of the vaporized drug is chemical heating, a battery is required to actuate the chemical reaction and / or control the electronic devices of the device.

[0078] vi) A "drug foil substrate" is an impermeable surface on which the drug is deposited to be heated and aerosolized. If electrical heating is used, more information about electrical heating can be found in WO2019152873, which is incorporated herein by reference. If chemical heating is used, it may be referred to as a chemical heating pack, and more information about chemical heating packs can be found in WO2004104492, which is incorporated herein by reference. The drug foil substrate defines a "drug foil substrate plane", which is sometimes preferably substantially parallel to the aerosol axis (223), i.e., defines an angle of -10 to 10°. The drug foil substrate can be planar or curved.

[0079] vii) "Solid drug film" refers to a layer containing a pure drug, two or more drugs, or a combination of one or more drugs and additional ingredients. Additional ingredients may include, for example, pharmaceutically acceptable excipients, carriers, etc.

[0080] viii) "Average Slope" is the slope of the straight line connecting the room temperature at time 0 and the target temperature for a given curve at the heating time.

[0081] ix) A "step function" is a line function with a very high slope (which tends to infinity). BRIEF DESCRIPTION OF THE DRAWINGS

[0082] Figure 1A Shown is apparatus 1: SS, a motorized benchtop screening apparatus.

[0083] Figure 1B A device 2 is shown: a handheld housing 1 .

[0084] Figure 1C A device 3 is shown: a handheld housing 2 .

[0085] Figure 1D Shown is heat source 1: test electric heating.

[0086] Figure 1E Shown is heat source 2: a chemical heat pack.

[0087] Figure 1F Heat source 3 is shown: electrical heating.

[0088] Figure 1G 3 is a graph showing the relationship between the purity of the emitted aerosol and the temperature of the drug foil substrate in Comparative Example 1.

[0089] Figure 2A and 2B A handheld medical device is shown that includes a disposable cartridge (200) and a handheld controller (100). Figure 2A In the embodiment, the air inlet (220) of the disposable cartridge is connected to the air inlet extension (103) of the handheld controller (100). Figure 2BIn the embodiment, the air inlet (220) of the disposable cartridge is directly connected to the atmosphere.

[0090] Figure 3A The time distribution within t_period1 is shown.

[0091] Figure 3B A drug foil substrate (205) resistance (R205) measurement circuit is shown.

[0092] Figure 4 A flow chart following the TP1 curve is shown.

[0093] Figure 5A , 5B 5C and 5D show four different t_period1 of one embodiment, where the temperature is measured based on the resistance of the drug foil substrate (205). These figures are not drawn to scale.

[0094] Fig. 6A An idealized graph of measured temperature (T_meas, solid line) and expected temperature (T_exp, dashed line) of one embodiment is shown, where when T_meas is above T_exp, the next t_period1 heats for 1 / 3 of the time t_period1-t_meas1. For simplicity, t_meas1 is not included in this graph.

[0095] Figure 6B An idealized graph of T_meas (solid line) and T_exp (dashed line) for one embodiment is shown, where each t_period1 is either heating or not heating. For simplicity, t_meas1 is not included in this graph.

[0096] Figure 7 A flow chart following the TP2 curve is shown.

[0097] Fig. 8A , 8B 8C and 8D show four t_period2 of one embodiment, where the temperature is measured based on the resistance of the drug foil substrate (205). These figures are not drawn to scale.

[0098] Fig. 9 A flow chart is shown which is followed by an apparatus embodying curves TP1 and TP2 .

[0099] Fig.10 A graph showing the temperature of a drug foil substrate (solid line) and T_exp of the drug foil substrate (dashed line) using an embodiment as described in Example 1. The temperature of the drug foil substrate was measured using a thermal imager (Thermacam A655sc, FLIR).

[0100] Fig.11A graph showing the temperature (solid line) and T_exp (dashed line) of the drug foil substrates for 9 drug foil substrates using an embodiment as described in Example 2. The temperature of the drug foil substrate was measured. DETAILED DESCRIPTION

[0101] Figure 2A A handheld medical device comprising a disposable cartridge (200) attached to a handheld controller (100) is shown. The disposable cartridge (200) comprises an air inlet (220), an airway (203) and an air outlet configured as a nozzle (202). The handheld controller (100) comprises a drug foil substrate heating circuit comprising a battery (101), a microcontroller (102) and an air inlet controller extension (103). The air inlet controller extension (103) and the air inlet (220) are fluidically connected. The handheld controller (100) and the disposable cartridge (200) are connected by an electrical connection (302) and an optional data connection (301) to share power and optional data.

[0102] Figure 2B and Figure 2A Similar, but without the air inlet control extension (103) in the handheld controller (100). The air inlet (220) in the disposable cartridge (200) may include a baffle and open directly to the atmosphere.

[0103] The first temperature curve (TP1) includes several t_period1, such as Figure 3A As shown, each t_period1 is divided into three different parts, one for heating (t_heat1), one for not applying any current (t_wait1), and one for measurement (t_meas). The ratio of t_heat1 to t_wait1 will depend on the specific situation, and it can even be all t_wait1 or all t_heat1. TP2 is divided in a similar way.

[0104] The temperature may be calculated by measuring the resistance on the drug foil substrate (205), optical measurement, direct contact measurement with a thermocouple, and / or any other known method.

[0105] For example, use Figure 3B The circuit shown measures the resistance of the pharmaceutical foil substrate using the well-known Ohm's Law formula:

[0106] V=I·R

[0107] Measurement circuit (see Figure 3B ) includes an XΩ resistor for reducing the measurement current to I_measA, which depends on the voltage (Vbattery) of the battery (101):

[0108] Measure a known resistor YΩ (see Figure 3B ) is used to measure I_meas, and the resistance of the resistor YΩ is selected to be close to the resistance of the drug foil substrate (205):

[0109] Using I_meas and the voltage drop V2-V1 around the drug foil substrate (see Figure 3B ), calculate the resistance (R205) of the drug foil substrate (205):

[0110] In summary, the resistance (R205) of the drug foil substrate (205) can be calculated as follows (see Figure 3B ):

[0111] R205=Y·(V2-V1) / (V4-V3)

[0112] The drug foil substrate has a resistance versus temperature relationship, i.e., has a different resistance at each temperature. This relationship can be determined for each drug foil substrate (or substrates) during disposable cartridge manufacturing by heating the drug foil substrate (205) to a set of predetermined temperatures and measuring the corresponding resistance and storing the relationship in the disposable cartridge.

[0113] Temperature may also be measured optically, ie by detecting the amount of infrared energy emitted by the medication foil substrate.During manufacture of the disposable cartridge, the emission characteristics may be determined for each medication foil substrate (or substrates) and the relationship stored in the disposable cartridge.

[0114] Temperature can also be measured by direct contact measurement using a thermocouple calibrated for the required temperature range.

[0115] Figure 4 TP1 is shown in the flowchart of the method. The method first heats during the t_heat1 time and does not apply current during the t_wait1 time ( Figure 5B ), or no current is applied during t_wait1, and then heating is performed during t_heat1 ( Figure 5C ), but any combination is possible, even distributing t_heat1 and t_wait1 in different parts (see Figure 5C ).

[0116] In TP1, one implementation is that one of t_heat1 and t_wait1 is 0 and the other is t_period1-t_meas1 (see Figure 5A and 5D ), but any combination is possible, for example, part of t_period1 is t_heat1 and another part is t_wait1 (see Figure 5B ), or even distribute t_heat1 and t_wait1 in different parts (see Figure 5C ). The value of t_period1 may change during TP1.

[0117] Figure 4 The next step in is to determine the temperature T_meas during t_meas1 (as described above). T_meas is compared to T_exp (expected temperature) at this moment according to the temperature-time relationship based on TP1, and the following t_heat1 and t_wait1 are set. If T_meas≤T_exp, then t_heat1=1% to 100% of (t_period1-t_meas1), and t_wait1=t_period1-t_meas1-t_heat1; otherwise, t_heat1=0% to 100% of (t_period1-t_meas1), and t_wait1=t_period1-t_meas1-t_heat1.

[0118] Figure 5A Display_period1, where t_wait1=0, and t_heat1=t_period1-t_meas.

[0119] For the second case, the ratio between t_heat1 and t_wait1 is chosen depending on the properties of the drug to be evaporated (sensitivity to temperature, enthalpy of evaporation, etc.). If it is desired that the temperature is not too much higher than T_exp, then if T_meas ≥ T_exp, then t_heat1 = 0 (e.g. Figure 5D The curve is similar to Figure 6B Representative curves are shown in Figure 6B In the first t_period1, t_wait1 = 0, which means t_heat1 = (t_period1-t_meas1). Figure 6B The same is true for the third, fourth, and sixth t_period1. Figure 6B In the second t_period1, t_heat1 = 0, which means t_wait1 = (t_period1-t_meas1). Figure 6B The same is true for the fifth t_period1.

[0120] Sometimes, it is preferred that the temperature is not too much lower than T_exp. Then, if T_meas ≥ T_exp, t_heat1 can be selected based on the temperature slope of the previous t_period1 so that at the end of the next t_period1, the temperature reaches the current T_exp ( Fig. 6A The dashed line in Fig. 6ARepresentative curves are shown in Fig. 6A In the first t_period1, t_wait1 = 0, which means t_heat1 = (t_period1-t_meas1). Fig. 6A The same is true for the third t_period1. Fig. 6A In the second t_period1, t_heat1 = 1 / 3 of (t_period1-t_meas1), which means t_wait1 = 2 / 3 of (t_period1-t_meas1). Fig. 6A The same is true for the fourth t_period1.

[0121] Any other ratio between t_heat1 and t_wait1 may be chosen depending on the drug to be vaporized. Furthermore, the ratio between t_heat1 and t_wait1 may vary during TP1, e.g., when approaching tTTP1, t_heat1 may need to be reduced and t_wait1 increased to avoid exceeding said tTTP1. Figure 5B and 5C Two possible options for allocating t_heat1 and t_wait1 are shown. Figure 5B In the example, t_heat1 is at the beginning of t_period1. Figure 5C In the example, t_heat1 and t_wait1 are distributed in two parts respectively.

[0122] This process is repeated until the desired temperature is reached (T_meas ≥ tTTP1) or the TP1 time (HtTP1) has elapsed.

[0123] If it is necessary to control the temperature for a longer time or follow a subsequent temperature curve after tTTP1 has been reached or HtTP1 ​​has passed, TP2 is followed.

[0124] Figure 7 The flowchart in FIG. 1 shows a flow chart of a method following TP2. The method first heats during t_heat2 and does not apply current during t_wait2 ( Figure 8B ), or no current is applied during t_wait2, and then heating is performed during t_heat2 ( Figure 8C ), but any combination is possible, even distributing t_heat2 and t_wait2 in different parts (see Figure 8C ).

[0125] In TP2, one implementation is that both t_heat2 and t_wait2 are not 0, and the other is t_period2-t_meas2 (see Fig.8D), but any combination is possible, for example, part of t_period2 is t_heat2 and another part is t_wait2 (see Figure 8B ), or even distribute t_heat2 and t_wait2 in different parts (see Figure 8C ). The value of t_period2 may change during TP2.

[0126] TP2( Figure 7 ) is to determine the temperature T_meas during t_meas2, similar to TP1.

[0127] Then, T_meas is compared with the expected temperature T_exp at this moment according to the temperature-time relationship based on TP2, and the following t_heat2 and t_wait2 are set. If T_meas≤T_exp, then t_wait2=0% to 98%, and t_heat1=1 to 98% of t_period2 (e.g. Figures 8A to 8C ); otherwise, t_wait2 = 1-99%, and t_heat1 = 0% to 98% of t_period1 (such as Figures 8A to 8D ).

[0128] For the second case, the ratio between t_heat2 and t_wait2 is chosen depending on the properties of the drug to be evaporated (sensitivity to temperature, enthalpy of evaporation, etc.). If it is desired that the temperature is not too much higher than T_exp, then if T_meas ≥ T_exp, then t_heat2 = 0 (e.g. Fig.8D The curve is similar to Figure 6B A representative curve of t_period1 is shown in . Sometimes, it is preferred that the temperature is not too much lower than T_exp, so if T_meas ≥ T_exp, t_heat1 can be selected based on the temperature slope of the previous t_period2 so that at the end of the next t_period2, T_exp is reached at that time, and its curve is similar to Fig. 6A A representative curve for t_period1 is shown in . Any other ratio between t_heat2 and t_wait2 may be chosen depending on the drug to be vaporized and may vary during TP2. Figure 8B and 8C Two possible options for allocating t_heat2 and t_wait2 are shown. Figure 8B In the example, t_heat2 is located at the beginning of t_period2. Figure 8C In the example, t_heat2 and t_wait2 are distributed in two parts respectively.

[0129] This process is repeated until the desired temperature is reached (T_meas ≥ tTTP2) or the TP2 time (HtTP2) has elapsed.

[0130] Fig. 9 The process of aerosol generation is shown, following curve TP1 once inhalation is detected and, when complete, optionally following curve TP2, when TP2 is complete, the heating is stopped.

[0131] A method for electrically heating a drug foil substrate (205) coated with a solid drug film (207) placed in a disposable cartridge (200) according to a first temperature-time relationship curve (TP1) to generate a condensation aerosol; the disposable cartridge (200) is suitable for being connected to a handheld controller (100);

[0132] TP1 includes:

[0133] a heating function having an average slope HSTP1 in the range of 1 to 5°C / ms; and

[0134] The target temperature tTTP1 ranges from 200 to 550°C, and / or

[0135] Heating time HtTP1, which ranges from 40 to 550 ms;

[0136] The method includes:

[0137] The adjustment phase includes:

[0138] During t_heat1, a current ITP1 is applied to the drug foil substrate (205), and during t_wait1, no current is applied.

[0139] No current is applied during t_wait1, and a current ITP1 is applied to the drug foil substrate (205) during t_heat1, or

[0140] The aforementioned t_wait1 and t_heat1 are distributed in alternating sections;

[0141] Determining the temperature (T_meas) of the drug foil substrate (205) during a period t_meas1 using a temperature sensor;

[0142] If T_meas ≤ T_exp, then

[0143] t_heat1 = 1% to 100% of (t_period1 - t_meas1), and t_wait1 = t_period1 - t_meas1 - t_heat1, otherwise

[0144] t_heat1 = 0% to 100% of (t_period1 - t_meas1), and t_wait1 = t_period1 - t_meas1 - t_heat1, where T_exp is based on TP1; and

[0145] Repeat steps a) to d) to match TP1 until tTTP1 is reached and / or HtTP1 ​​has passed;

[0146] in:

[0147] The control cycle time t_period1 ranges from 0.5 to 5 ms.

[0148] The measurement time t_meas1 ranges from 1% to 40% of t_period1,

[0149] T_exp is based on the expected temperature of TP1 at any given point in time,

[0150] t_period1=t_heat1+t_wait1+t_meas1,

[0151] t_period1 is the length of time for each cycle of measuring temperature and optionally heating the drug foil substrate (205),

[0152] t_heat1 is the time for heating the drug foil substrate (205) within each t_period1,

[0153] t_wait1 is the time during which the drug foil substrate (205) is not heated within each t_period1.

[0154] t_meas1 is the time at which the temperature of the drug foil substrate (205) is measured within each t_period1, and

[0155] The current ITP1 is 30 to 400A,

[0156] The method of the aforementioned embodiment further includes a second temperature versus time relationship curve (TP2) performed immediately after TP1 ends;

[0157] TP2 includes:

[0158] a heating function having an average slope HSTP2 in the range of -0.15 to 0.15°C / ms; and

[0159] The target temperature tTTP1 is in the range of 200 to 400°C, and / or

[0160] Heating time HtTP1, which ranges from 0.5 to 2000 ms;

[0161] The method includes:

[0162] The adjustment phase includes:

[0163] During t_heat2, a current ITP2 is applied to the drug foil substrate (205), and during t_wait2, no current is applied.

[0164] No current is applied during t_wait2, and a current ITP2 is applied to the drug foil substrate (205) during t_heat2, or

[0165] The aforementioned t_wait2 and t_heat2 are distributed in alternating sections;

[0166] Determine the temperature of the drug foil substrate during t_meas2 using a temperature sensor (T_meas);

[0167] If T_meas ≤ T_exp, then

[0168] t_heat2 = 1% to 100% of (t_period2 - t_meas2), and t_wait2 = t_period2 - t_meas2 - t_heat2, otherwise

[0169] t_heat2 = 0% to 100% of (t_period2 - t_meas2), and t_wait2 = t_period2 - t_meas2 - t_heat2, where T_exp is based on TP2; and

[0170] Repeat steps A) to D) to match TP2 until tTTP2 is reached and / or HtTP2 has passed;

[0171] in

[0172] The control cycle time t_period2 ranges from 0.5 to 5 ms.

[0173] The measurement time t_meas2 ranges from 1% to 40% of t_period2,

[0174] t_period2=t_heat2+t_wait2+t_meas2,

[0175] t_period2 is the length of time for each cycle of measuring temperature and optionally heating the drug foil substrate (205),

[0176] t_heat2 is the time for heating the drug foil substrate (205) within each t_period2,

[0177] t_wait2 is the time during which the drug foil substrate (205) is not heated within each t_period2.

[0178] t_meas2 is the time at which the temperature of the drug foil substrate (205) is measured within each t_period2, and

[0179] The current ITP2 ranges from 10 to 50A.

[0180] The method according to any of the preceding embodiments, wherein the heating function in TP1 is a straight line, a power function, a polynomial function, a step function or a logarithmic function; or in another embodiment, the function is a straight line.

[0181] The method according to any of the preceding embodiments, wherein HSTP1 ranges from 1.25 to 4.5°C / ms, in another embodiment from 1.5 to 4.0°C / ms, in another embodiment from 1.75 to 3.5°C / ms, or in another embodiment from 1.75 to 3.0°C / ms.

[0182] The method according to any of the preceding embodiments, wherein tTTP1 ranges from 200 to 400°C, in another embodiment from 225 to 390°C, in another embodiment from 250 to 380°C, in another embodiment from 275 to 370°C, or in another embodiment from 300 to 360°C.

[0183] The method according to any of the preceding embodiments, wherein HtTP1 ​​ranges from 40 to 400 ms, in another embodiment from 50 to 350 ms, in another embodiment from 75 to 300 ms, in another embodiment from 90 to 250 ms, in another embodiment from 100 to 200 ms, or in another embodiment from 125 to 180 ms.

[0184] The method according to any of the preceding embodiments, wherein t_period1 ranges from 0.55 to 4.0 ms, in another embodiment from 0.6 to 3.5 ms, in another embodiment from 0.7 to 3.0 ms, in another embodiment from 0.75 to 2.5 ms, in another embodiment from 0.8 to 2.0 ms, or in another embodiment from 0.9 to 1.75 ms.

[0185] The method according to any of the preceding embodiments, wherein t_meas1 ranges from 5% to 35% of t_period1, in another embodiment from 10% to 30% of t_period1, in another embodiment from 15% to 25% of t_period1, or in another embodiment from 15% to 22% of t_period1.

[0186] The method according to any of the preceding embodiments, wherein ITP1 ranges from 30 to 300A, in another embodiment from 50 to 290A, in another embodiment from 75 to 280A, in another embodiment from 100 to 280A, in another embodiment from 125 to 260A, in another embodiment from 150 to 250A, or in another embodiment from 175 to 240A.

[0187] A method according to any of the preceding embodiments, wherein when T_meas is lower than tTTP1, then c) is, if T_meas≤T_exp, then t_heat1=90100% of (t_period1-t_meas1), and t_wait1=t_period1-t_meas1-t_heat1, otherwise, t_heat1=0% of (t_period1-t_meas1), and t_wait1=t_period1-t_meas1-t_heat1.

[0188] A method according to any of the preceding embodiments, wherein when T_meas is higher than tTTP1–50°C and lower than tTTP1–20°C, then c) is, if T_meas≤T_exp, then t_heat1=7090% of (t_period1-t_meas1), and t_wait1=t_period1-t_meas1-t_heat1, otherwise, t_heat1=0% of (t_period1-t_meas1), and t_wait1=t_period1-t_meas1-t_heat1.

[0189] A method according to any of the preceding embodiments, wherein when T_meas is higher than tTTP1–20°C, then c) is, if T_meas≤T_exp, then t_heat1=40% to 60% of (t_period1-t_meas1), and t_wait1=t_period1-t_meas1-t_heat1, otherwise, t_heat1=0% of (t_period1-t_meas1), and t_wait1=t_period1-t_meas1-t_heat1.

[0190] According to the method of any of the foregoing embodiments, when T_meas is lower than tTTP1-50°C, step c) is

[0191] a) If T_meas≤T_exp, t_heat1=2% to 100% of (t_period1-t_meas1), and t_wait1=t_period1t_meas1t_heat1, otherwise, t_heat1=0 to 80% of (t_period1-t_meas1), and t_wait1=t_period1-t_meas1-t_heat1;

[0192] b) In another embodiment, if T_meas≤T_exp, t_heat1=4% to 100% of (t_period1-t_meas1), and t_wait1=t_period1-t_meas1-t_heat1, otherwise, t_heat1=0% to 60% of (t_period1-t_meas1), and t_wait1=t_period1-t_meas1-t_heat1;

[0193] c) In another embodiment, if T_meas≤T_exp, t_heat1=6% to 100% of (t_period1-t_meas1), and t_wait1=t_period1-t_meas1-t_heat1, otherwise, t_heat1=0% to 40% of (t_period1-t_meas1), and t_wait1=t_period1-t_meas1-t_heat1;

[0194] d) In another embodiment, if T_meas≤T_exp, t_heat1=8% to 100% of (t_period1-t_meas1), and t_wait1=t_period1-t_meas1-t_heat1, otherwise, t_heat1=0% to 20% of (t_period1-t_meas1), and t_wait1=t_period1-t_meas1-t_heat1;

[0195] e) In another embodiment, if T_meas≤T_exp, t_heat1=100% of (t_period1-t_meas1), and t_wait1=t_period1-t_meas1-t_heat1, otherwise, t_heat1=0% to 20% of (t_period1-t_meas1), and t_wait1=t_period1-t_meas1-t_heat1;

[0196] f) In another embodiment, if T_meas≤T_exp, then t_heat1=100% of (t_period1-t_meas1), and t_wait1=t_period1-t_meas1-t_heat1, otherwise, t_heat1=0% of (t_period1-t_meas1), and t_wait1=t_period1-t_meas1-t_heat1,

[0197] g) In another embodiment, if T_meas≤T_exp, then t_heat1=70% to 90% of (t_period1-t_meas1), and t_wait1=t_period1-t_meas1-t_heat1, otherwise, t_heat1=0% of (t_period1-t_meas1), and t_wait1=t_period1-t_meas1-t_heat1; or

[0198] h) In another embodiment, if T_meas≤T_exp, t_heat1=40% to 60% of (t_period1-t_meas1), and t_wait1=t_period1-t_meas1-t_heat1, otherwise, t_heat1=0% of (t_period1-t_meas1), and t_wait1=t_period1-t_meas1-t_heat1.

[0199] The method according to any one of embodiments 2 to 13, wherein the heating function in TP2 is a straight line, a power function, a polynomial function, a step function or a logarithmic function; in another embodiment, the function is a straight line.

[0200] The method according to any one of embodiments 2 to 14, wherein HSTP2 ranges from -0.13 to 0.13°C / ms, in another embodiment -0.1 to 0.1°C / ms, in another embodiment -0.08 to 0.08°C / ms, or in another embodiment -0.05 to 0.08°C / ms.

[0201] The method according to any one of embodiments 2 to 15, wherein tTTP2 ranges from 200 to 400°C, in another embodiment from 225 to 390°C, in another embodiment from 250 to 380°C, in another embodiment from 275 to 370°C, or in another embodiment from 300 to 360°C.

[0202] The method according to any one of embodiments 2 to 16, wherein the range of HtTP2 is 0.5 to 1500 ms, in another embodiment 0.5 to 1000 ms, in another embodiment 1.5 to 500 ms, in another embodiment 2.5 to 250 ms, in another embodiment 3.0 to 125 ms, in another embodiment 4.5 to 75 ms, in another embodiment 5.0 to 50 ms, or in another embodiment 5.5 to 25 ms.

[0203] The method according to any one of embodiments 2 to 17, wherein t_period2 ranges from 0.55 to 4.0 ms, in another embodiment from 0.6 to 3.5 ms, in another embodiment from 0.7 to 3.0 ms, in another embodiment from 0.75 to 2.5 ms, in another embodiment from 0.8 to 2.0 ms, or in another embodiment from 0.9 to 1.75 ms.

[0204] The method according to any one of embodiments 2 to 18, wherein t_meas2 ranges from 5% to 35% of t_period2, in another embodiment from 10% to 30% of t_period2, in another embodiment from 15% to 25% of t_period2, or in another embodiment from 15% to 22% of t_period2.

[0205] The method according to any one of embodiments 2 to 19, wherein ITP2 ranges from 12 to 45 A, in another embodiment from 15 to 40 A, in another embodiment from 17 to 35 A, in another embodiment from 20 to 30 A, or in another embodiment from 22 to 27 A.

[0206] The method according to any one of embodiments 2 to 20, wherein step C) is

[0207] a) If T_meas≤T_exp, t_heat2=2% to 80% of (t_period2-t_meas2), and t_wait2=t_period2t_meas2t_heat2, otherwise, t_heat2=0% to 80% of (t_period2-t_meas2), and t_wait2=t_period2-t_meas2-t_heat2;

[0208] b) In another embodiment, if T_meas≤T_exp, t_heat2=4% to 60% of (t_period2-t_meas2), and t_wait2=t_period2-t_meas2-t_heat2, otherwise, t_heat2=0% to 60% of (t_period2-t_meas2), and t_wait2=t_period2-t_meas2-t_heat2;

[0209] c) In another embodiment, if T_meas≤T_exp, t_heat2=6% to 40% of (t_period2-t_meas2), and t_wait2=t_period2-t_meas2-t_heat2, otherwise, t_heat2=0% to 40% of (t_period2-t_meas2), and t_wait2=t_period2-t_meas2-t_heat2;

[0210] d) In another embodiment, if T_meas≤T_exp, t_heat2=8% to 20% of (t_period2-t_meas2), and t_wait2=t_period2-t_meas2-t_heat2, otherwise, t_heat2=0% to 20% of (t_period2-t_meas2), and t_wait2=t_period2-t_meas2-t_heat2; and

[0211] e) In another embodiment, if T_meas≤T_exp, t_heat2=8% to 15% of (t_period2-t_meas2), and t_wait2=t_period2-t_meas2-t_heat2, otherwise, t_heat2=0% of (t_period2-t_meas2), and t_wait2=t_period2-t_meas2-t_heat2.

[0212] The method according to any of the preceding embodiments, wherein the resistance of the drug foil substrate (205) ranges from 1 to 200 mΩ, in another embodiment from 5 to 100 mΩ, in another embodiment from 10 to 75 mΩ, in another embodiment from 12 to 50 mΩ, in another embodiment from 12 to 20 mΩ, or in another embodiment from 13 to 20 mΩ.

[0213] The method according to any of the preceding embodiments, wherein the drug foil substrate (205) is a metallic drug foil substrate (205).

[0214] According to the method of the aforementioned embodiment, the metal drug foil substrate (205) is a stainless steel drug foil substrate (205).

[0215] The method according to any of the preceding embodiments, wherein the temperature sensor is selected from measuring electrical resistance on the drug foil substrate (205), optical measurement, and / or direct contact measurement with a thermocouple.

[0216] The method according to the preceding embodiment, wherein the temperature sensor measures the electrical resistance on the drug foil substrate (205).

[0217] A method according to the aforementioned embodiment, wherein T_meas is measured by applying a measurement current I_meas to the drug foil substrate (205), and the range of I_meas is 0.1 to 20A, in another embodiment 0.5 to 15A, in another embodiment 1 to 10A, in another embodiment 1.5 to 7A, or in another embodiment 2 to 5A.

[0218] The method according to any one of embodiments 26 to 27, wherein the predetermined temperature and resistance relationship of the drug foil substrate (205) is stored in a memory (230) of the disposable cartridge (200).

[0219] A method according to the aforementioned embodiment, wherein the temperature sensor measures the resistance on the drug foil substrate (205), T_meas is measured by applying a measurement current I_meas to the drug foil substrate (205), and the range of I_meas is 0.1 to 20A, in another embodiment 0.5 to 15A, in another embodiment 1 to 10A, in another embodiment 1.5 to 7A, or in another embodiment 2 to 5A.

[0220] The method according to any of the preceding embodiments, wherein HSTP1, tTTP1, and / or HtTP1 ​​are stored in a memory (230) of the disposable cartridge (200).

[0221] The method according to any one of embodiments 2 to 30, wherein HSTP2, tTTP2, and / or HtTP2 are stored in a memory (230) of the disposable cartridge (200).

[0222] The method according to any of the preceding embodiments, wherein the voltage is 3 to 13V, in another embodiment the voltage is 3 to 4V, in another embodiment the voltage is 6 to 8V, or in another embodiment the voltage is 10 to 12V.

[0223] A disposable cartridge (200) configured to perform the method of any of the preceding embodiments and adapted to be connected to a handheld controller (100) of any of embodiments 39 to 45, the disposable cartridge (200) comprising:

[0224] an air inlet (220) located at one end of the airway (203);

[0225] an air outlet (202) at the other end of the airway (203), which is configured as a nozzle;

[0226] a drug foil substrate (205) having a water-impermeable surface, with or without perforations, placed within the airway (203);

[0227] a drug foil substrate support (204);

[0228] A solid drug film (207) coated on a drug foil substrate (205); and

[0229] An electrical connection (302) and / or a data connection (301) between a disposable cartridge (200) and a handheld controller (100) of any one of embodiments 39 to 45.

[0230] The disposable cartridge (200) of the aforementioned embodiment further comprises a memory (230) and a data connection (301) between the memory and the handheld controller (100) of any one of embodiments 39 to 45.

[0231] The disposable cartridge (200) of the aforementioned embodiment, wherein the memory (230) is a long-term memory (including volatile, non-volatile or semi-volatile memory), a barcode, a QR code or an RFID.

[0232] The disposable cartridge (200) of any one of embodiments 34 to 35, wherein the memory (230) comprises a temperature versus electrical resistance relationship of the drug foil substrate (205).

[0233] The disposable cartridge (200) of any one of embodiments 33 to 36, wherein the reservoir (230) comprises HSTP1, tTTP1, and / or HtTP1.

[0234] The disposable cartridge (200) of any one of embodiments 33 to 37, wherein the reservoir (230) comprises HSTP2, tTTP2, and / or HtTP2.

[0235] A handheld controller (100) configured to perform the methods of embodiments 1 to 31 and adapted to be connected to a disposable cartridge (200) of embodiments 33 to 38, comprising:

[0236] at least one battery (101),

[0237] at least one microcontroller (102); and

[0238] An electrical connection (302) and / or a data connection (301) between at least one battery (101), at least one microcontroller (102), and the disposable cartridge (200) of embodiments 33 to 38.

[0239] The handheld controller of the aforementioned embodiment, wherein at least one battery (101) is capable of providing 3 to 12V, in another embodiment 4 to 11V, in another embodiment 5 to 10V, in another embodiment 6 to 10V, or in another embodiment 7 to 9V.

[0240] A handheld controller (100) according to any one of embodiments 39 to 40, wherein at least one battery (101) is capable of delivering a peak current greater than 30A, in another embodiment greater than 50A, in another embodiment greater than 75A, in another embodiment greater than 100A, in another embodiment greater than 125A, in another embodiment greater than 150A, or in another embodiment greater than 175A.

[0241] The handheld controller (100) of any one of embodiments 39 to 41, further comprising an airflow sensor that triggers heating of the medication foil substrate (205).

[0242] The handheld controller (100) of the aforementioned embodiment, wherein the airflow sensor is selected from a differential pressure sensor, one or more thermistors, an airflow or sail switch, a hot wire anemometer or a vane anemometer.

[0243] A handheld controller (100) according to any one of embodiments 42 to 43, wherein the airflow sensor triggers heating of the medicine foil substrate when the airflow is above 7 L / min; in another embodiment, triggers heating of the medicine foil substrate when the airflow is above 14 L / min; in another embodiment, triggers heating of the medicine foil substrate when the airflow is above 20 L / min; in another embodiment, triggers heating of the medicine foil substrate when the airflow is above 30 L / min, or in another embodiment, triggers heating of the medicine foil substrate when the airflow is 7 to 35 L / min.

[0244] The handheld controller (100) of any one of embodiments 39 to 44 or the disposable cartridge (200) of any one of embodiments 33 to 38 for use in treatment.

[0245] The method according to any one of embodiments 1 to 31, the handheld controller (100) of any one of embodiments 39 to 45, or the disposable cartridge (200) of any one of embodiments 33 to 38 for a condition or episode, wherein the drug in the solid drug film (207) is selected from:

[0246] Loxapine or a pharmaceutically acceptable salt thereof, wherein the condition or episode is agitation, including:

[0247] Rapid control of mild to moderate agitation in adults with schizophrenia or bipolar disorder, or

[0248] acute agitation associated with schizophrenia or bipolar disorder;

[0249] alprazolam, estazolam, or a pharmaceutically acceptable salt thereof, wherein the condition or seizure is epilepsy, wherein epilepsy comprises seizures;

[0250] Fentanyl or a pharmaceutically acceptable salt thereof, wherein the condition or onset is breakthrough pain;

[0251] Zaleplon, amorant or a pharmaceutically acceptable salt thereof, wherein the condition or episode is a sleep disorder, including:

[0252] Waking up in the middle of the night, or

[0253] Insomnia in the middle of the night;

[0254] Apomorphine, pergolide, ropinirole, pramipexole or a pharmaceutically acceptable salt thereof, wherein the condition or attack is Parkinson's disease, non-attack period of Parkinson's disease and / or idiopathic Parkinson's disease;

[0255] Granisetron, ondansetron, palonosetron or a pharmaceutically acceptable salt thereof, wherein the condition or episode is:

[0256] nausea,

[0257] vomiting, or

[0258] Cyclic vomiting syndrome;

[0259] Nicotine or a pharmaceutically acceptable salt thereof, including nicotine meta-salicylate, wherein the condition or episode is nicotine addiction and / or smoking cessation; or

[0260] Ropinirole, pramipexole, or rotigotine, and the condition or episode is restless legs syndrome.

[0261] A method for treating a condition or attack, comprising administering a drug contained in a solid drug film (207), the solid drug film (207) being coated on at least a portion of a drug foil substrate (205), the drug foil substrate (205) being the drug foil substrate (205) of the method according to any one of embodiments 1 to 31, the handheld controller (100) according to any one of embodiments 39 to 45, or the disposable cartridge (200) according to any one of embodiments 33 to 38, wherein the drug in the solid drug film (207) is selected from:

[0262] Loxapine or a pharmaceutically acceptable salt thereof, wherein the condition or episode is agitation, including:

[0263] Rapid control of mild to moderate agitation in adults with schizophrenia or bipolar disorder, or

[0264] acute agitation associated with schizophrenia or bipolar disorder;

[0265] alprazolam, estazolam, or a pharmaceutically acceptable salt thereof, wherein the condition or seizure is epilepsy, wherein epilepsy comprises seizures;

[0266] Fentanyl or a pharmaceutically acceptable salt thereof, wherein the condition or onset is breakthrough pain;

[0267] Zaleplon, amorant or a pharmaceutically acceptable salt thereof, wherein the condition or episode is a sleep disorder, including:

[0268] Waking up in the middle of the night, or

[0269] Insomnia in the middle of the night;

[0270] Apomorphine, pergolide, ropinirole, pramipexole or a pharmaceutically acceptable salt thereof, wherein the condition or attack is Parkinson's disease, non-attack period of Parkinson's disease and / or idiopathic Parkinson's disease;

[0271] Granisetron, ondansetron, palonosetron or a pharmaceutically acceptable salt thereof, wherein the condition or episode is:

[0272] nausea,

[0273] vomiting, or

[0274] Cyclic vomiting syndrome;

[0275] Nicotine or a pharmaceutically acceptable salt thereof, including nicotine meta-salicylate, wherein the condition or episode is nicotine addiction and / or smoking cessation; or

[0276] Ropinirole, pramipexole, or rotigotine, and the condition or episode is restless legs syndrome.

[0277] Use of the method according to any one of embodiments 1 to 31, the handheld controller (100) of any one of embodiments 39 to 45 (the preceding embodiments), or the disposable cartridge (200) of any one of embodiments 33 to 38 in the manufacture of a medicament for treating a condition or attack, wherein the drug in the solid drug film (207) is selected from:

[0278] Loxapine or a pharmaceutically acceptable salt thereof, wherein the condition or episode is agitation, including:

[0279] Rapid control of mild to moderate agitation in adults with schizophrenia or bipolar disorder, or

[0280] acute agitation associated with schizophrenia or bipolar disorder;

[0281] alprazolam, estazolam, or a pharmaceutically acceptable salt thereof, wherein the condition or seizure is epilepsy, wherein epilepsy comprises seizures;

[0282] Fentanyl or a pharmaceutically acceptable salt thereof, wherein the condition or onset is breakthrough pain;

[0283] Zaleplon, amorant or a pharmaceutically acceptable salt thereof, wherein the condition or episode is a sleep disorder, including:

[0284] Waking up in the middle of the night, or

[0285] Insomnia in the middle of the night;

[0286] Apomorphine, pergolide, ropinirole, pramipexole or a pharmaceutically acceptable salt thereof, wherein the condition or attack is Parkinson's disease, non-attack period of Parkinson's disease and / or idiopathic Parkinson's disease;

[0287] Granisetron, ondansetron, palonosetron or a pharmaceutically acceptable salt thereof, wherein the condition or episode is:

[0288] nausea,

[0289] vomiting, or

[0290] Cyclic vomiting syndrome;

[0291] Nicotine or a pharmaceutically acceptable salt thereof, including nicotine meta-salicylate, wherein the condition or episode is nicotine addiction and / or smoking cessation; or

[0292] Ropinirole, pramipexole, or rotigotine, and the condition or episode is restless legs syndrome.

[0293] The medicament for use in the method according to any one of embodiments 1 to 31, the handheld controller (100) of any one of embodiments 39 to 45 (the preceding embodiments), or the disposable cartridge (200) of any one of embodiments 33 to 38 comprises a drug selected from the group consisting of loxapine, alprazolam, estazolam, fentanyl, zaleplon, amorant, apomorphine, pergolide, ropinirole, pramipexole, granisetron, ondansetron, palonosetron, nicotine, nicotine meta-salicylate, rotigotine, or a pharmaceutically acceptable salt thereof.

[0294] A drug deposited on a drug foil substrate (205) for a condition or episode, the drug foil substrate (205) being a drug foil substrate (205) of a method according to any one of embodiments 1 to 31, a handheld controller (100) according to any one of embodiments 39 to 45, or a disposable cartridge (200) according to any one of embodiments 33 to 38, wherein when the drug is:

[0295] Loxapine or a pharmaceutically acceptable salt thereof, wherein the condition or episode is agitation, including:

[0296] Rapid control of mild to moderate agitation in adults with schizophrenia or bipolar disorder, or

[0297] acute agitation associated with schizophrenia or bipolar disorder;

[0298] alprazolam, estazolam, or a pharmaceutically acceptable salt thereof, wherein the condition or seizure is epilepsy, wherein epilepsy comprises seizures;

[0299] Fentanyl or a pharmaceutically acceptable salt thereof, wherein the condition or onset is breakthrough pain;

[0300] Zaleplon, amorant or a pharmaceutically acceptable salt thereof, wherein the condition or episode is a sleep disorder, including:

[0301] Waking up in the middle of the night, or

[0302] Insomnia in the middle of the night;

[0303] Apomorphine, pergolide, ropinirole, pramipexole or a pharmaceutically acceptable salt thereof, wherein the condition or attack is Parkinson's disease, non-attack period of Parkinson's disease and / or idiopathic Parkinson's disease;

[0304] Granisetron, ondansetron, palonosetron or a pharmaceutically acceptable salt thereof, wherein the condition or episode is:

[0305] nausea,

[0306] vomiting, or

[0307] Cyclic vomiting syndrome;

[0308] Nicotine or a pharmaceutically acceptable salt thereof, including nicotine meta-salicylate, wherein the condition or episode is nicotine addiction and / or smoking cessation; or

[0309] Ropinirole, pramipexole, or rotigotine, and the condition or episode is restless legs syndrome.

[0310] Example

[0311] i) Infrared temperature measurement

[0312] ii) Temperature measurements were made using FLIR Systems infrared cameras Thermacam SC3000 and A655sc. The SC3000 infrared camera uses quantum well infrared photodetector technology and the A655sc uses an uncooled microbolometer detector. These cameras have high sensitivity and accuracy, capturing images up to 180Hz and 200Hz, respectively. The temperature is calculated based on the amount of infrared light emitted. The cameras were calibrated by heating a metal cylinder (resistive heating using a constant current DC power supply) to various steady-state temperatures between 200 and 400°C and measuring the actual temperature using calibrated thermocouples (Omega, Stamford, CT).

[0313] iii) Device 1: SS, electric bench-top screening device

[0314] iv) If Figure 1A As shown, the heat source 1 in the test device is mechanically and electrically connected. The device 1 has an air inlet and outlet and a 1F capacitor (Phoenix Gold Titanium series) for discharge to resistively heat the substrate (<0.2 seconds) and promote rapid aerosol formation by a transverse foil airflow of about 30 L / min. The calibration of temperature and applied voltage is determined by a thermocouple spot welded to the foil surface.

[0315] v) Device 2: Handheld housing 1

[0316] vi) Devices with a length of 100 mm, e.g. Figure 1B The device in the shape of The same device, by Molded from resin (antistatic material).

[0317] vii) Device 3: Handheld housing 2

[0318] viii) Devices with a length of 89 mm, e.g. Figure 1C The device in Molded from resin (antistatic material).

[0319] ix) Heat source 1: Test electric heating

[0320] x) 12.7 x 63.5, 0.127 mm 304 stainless steel drug foil substrate is attached to the device 1 and receives electrical power from a power source through a connector. The device is actuated with a constant airflow of approximately 30 L / min. Figure 1D An embodiment is described in .

[0321] xi) Heat source 2: Chemical heat pack

[0322] xii) A 47.2 x 47.2 x 0.38 mm 304 stainless steel drug foil substrate is attached to a chemical heat pack connected to device 2. Figure 1E A chemical heat pack is shown.

[0323] xiii) Information on chemical heat packs can be found in WO2004104492, which is incorporated herein by reference.

[0324] xiv) In the chemical heat pack device, the exothermic thermite reaction of the reactants in the heat pack propagates rapidly (about 0.1 seconds) and generates heat almost instantly, thereby evaporating the drug film. The reactants are calibrated to heat the drug foil substrate to a given temperature. The upper and lower shells are welded before evaporation. The device is actuated with a constant airflow of about 30 L / min.

[0325] xv) Heat source 3: Electric heating

[0326] xvi) 31 x 28 x 0.127 mm 304 stainless steel drug foil substrate with electrical connections (e.g. Figure 1F The base in ( ) is connected to the device 3. The device 3 is attached to a handheld controller, such as the controller described in WO2019152873.

[0327] Comparative Example 1:

[0328] mg of apomorphine hydrochloride (APO) was coated on the drug foil substrate of heat source 1 or 2, with an area of ​​2.27 cm 2 (0.44mg / cm 2 ) and heat to the temperature specified in the table below.

[0329]

[0330] The data is plotted on Figure 1G , the graph generally shows that the higher the temperature, the higher the evaporation % and the lower the aerosol purity.

[0331] Embodiment 1:

[0332] The uncoated drug foil substrate of heat source 3 is modified to include a calcium fluoride window (transparent to infrared light) and is heated using the following method, in which if T_meas≤T_exp, then t_heat1=t_period1-t_meas1, otherwise t_wait1=t_period1-t_meas1. In this embodiment, HSTP1 is 1.5°C / ms, tTTP1 is 350°C, t_period_1 is 1.3ms, and t_meas1 is 0.3ms. The temperature is measured using the resistance-temperature relationship of the drug foil substrate, and the circuit used is as follows: Figure 3B As shown, the error is ±3°C.

[0333] When T_meas is close to tTTP1, then when T_meas≤T_exp, t_heat1=10%(t_period1-t_meas1), otherwise t_wait1=t_period1-t_meas1, in order to obtain a smoother curve and prevent the drug foil substrate from overheating. This is why Fig.10 The graph in shows a soft curve before starting TP2.

[0334] For TP2, HSTP2 is -0.05°C / ms and tTTP2 is 313°C.

[0335] Fig.10 A graph showing T_exp (dashed line) and the temperature measured in an infrared temperature measurement. The measured temperature is very close to T_exp, the difference is due to the different measurement methods.

[0336] Embodiment 2:

[0337] The same apparatus and conditions as in Example 1 were used, but HSTP1 = 2.0° C. / ms, tTTP1 = 309° C., HSTP2 = 0° C. / ms, and tTTP2 was 309° C. Nine different uncoated drug foil substrates were used.

[0338] Fig.11 A graph showing T_exp (dashed line) and the temperature measured in an infrared temperature measurement. The measured temperature is very close to T_exp, the difference is due to the different measurement methods.

[0339] The meanings of the reference numerals in the figures are:

[0340] 100: Handheld controller.

[0341] 101:Battery.

[0342] 102: Microcontroller.

[0343] 103: Air intake controller extension.

[0344] 200: Single-dose disposable cartridge.

[0345] 202: Suitable as an air outlet for a suction nozzle.

[0346] 203: Air passage defined by the inner wall.

[0347] 204: Drug foil substrate support.

[0348] 205: Medicated foil substrate.

[0349] 207: Solid drug film.

[0350] 220: Air intake.

[0351] 230: Disposable cartridge storage.

[0352] 301: Data connection between the handheld controller (100) and the disposable cartridge (200).

[0353] 302: Electrical connection between the handheld controller (100) and the disposable cartridge (200).

[0354] List of variables:

[0355] T_meas: The temperature measured during any t_meas1 or t_meas2 period.

[0356] T_exp: The expected temperature at any given moment when following TP1 or TP2.

[0357] TP1: The first temperature and time relationship curve.

[0358] HSTP1: average heating slope in TP1.

[0359] tTTP1: Target temperature in TP1.

[0360] HtTP1: Heating time in TP1.

[0361] t_period1: The length of the feedback period divided by TP1.

[0362] t_heat1: The time the drug foil substrate (205) is heated following TP1, which is a portion of t_period1.

[0363] t_wait1: The time following TP1 during which the drug foil substrate (205) is not heated and its temperature is not measured, which is a portion of t_period1.

[0364] t_meas1: The time at which the temperature of the drug foil substrate (205) is measured following TP1, which is a portion of t_period1.

[0365] ITP1: The current used to heat the drug foil substrate (205) following TP1.

[0366] TP2: The second temperature and time relationship curve.

[0367] HSTP2: Heating slope in TP2.

[0368] tTTP2: Target temperature in TP2.

[0369] HtTP2: Heating time in TP2.

[0370] t_period2: The length of the feedback period divided by TP2.

[0371] t_heat2: The time the drug foil substrate (205) is heated following TP2, which is a portion of t_period2.

[0372] t_wait2: The time following TP2 during which the drug foil substrate (205) is not heated and its temperature is not measured, which is part of t_period2.

[0373] t_meas2: The time at which the temperature of the drug foil substrate (205) is measured following TP2, which is a portion of t_period2.

[0374] ITP2: The current used to heat the drug foil substrate (205) following TP2.

[0375] I_meas: The current used when measuring the temperature of the drug foil substrate (205) using the technique of measuring the resistance on the drug foil substrate (205).

[0376] The various embodiments are for purposes of example only and are not intended to be limiting.

Claims

1. A method for electrically heating a drug foil substrate (205) coated with a solid drug film (207) placed in a disposable cartridge (200) according to a first temperature-time relationship curve (TP1) to generate a condensation aerosol ； The disposable cartridge (200) is adapted to be connected to a handheld controller (100); TP1 includes: ■ a heating function with an average slope HSTP1 in the range of 1°C / ms to 5°C / ms; and ■ target temperature tTTP1, which ranges from 200°C to 550°C, and / or ■Heating time HtTP1, which ranges from 40ms to 550ms; The method comprises: a. Adjustment phase, including: ■ During t_heat1, a current ITP1 is applied to the drug foil substrate (205), and during t_wait1, no current is applied, ■ No current is applied during t_wait1, and a current ITP1 is applied to the drug foil substrate (205) during t_heat1, or ■ The aforementioned t_wait1 and t_heat1 are distributed in alternating sections; b. using a temperature sensor to determine the temperature (T_meas) of the drug foil substrate (205) during t_meas1; c. If T_meas ≤ T_exp, then t_heat1 = 1% to 100% of (t_period1 - t_meas1), and t_wait1 = t_period1 - t_meas1 - t_heat1, otherwise t_heat1 = 0% to 100% of (t_period1 - t_meas1), and t_wait1 = t_period1 - t_meas1 - t_heat1, where T_exp is based on TP1; and d. Repeat steps a) to d) to match TP1 until tTTP1 is reached and / or HtTP1 ​​has passed; in: ■The control cycle time t_period1 ranges from 0.5ms to 5ms, ■The measurement time t_meas1 ranges from 1% to 40% of t_period1, ■T_exp is based on the expected temperature of TP1 at any given point in time, ■t_period1=t_heat1+t_wait1+t_meas1, ■ t_period1 is the length of time for each cycle of measuring temperature and optionally heating the drug foil substrate (205), ■ t_heat1 is the time for heating the drug foil substrate (205) within each t_period1, ■ t_wait1 is the time during which the drug foil substrate (205) is not heated within each t_period1, ■ t_meas1 is the time at which the temperature of the drug foil substrate (205) is measured within each t_period1, and ■The current ITP1 is 30A to 400A.

2. The method according to the preceding claim, further comprising a second temperature versus time curve (TP2) after the end of TP1; TP2 include: ■ Heating function, whose average slope HSTP2 ranges from -0.15°C / ms to 0.15°C / ms; and ■ target temperature tTTP2, which ranges from 200°C to 550°C, and / or ■Heating time HtTP2, ranging from 0.5ms to 2000ms; The method comprises: A. Adjustment phase, including: ■ during t_heat2, a current ITP2 is applied to the drug foil substrate (205), and during t_wait2, no current is applied, ■ No current is applied during t_wait2, and a current ITP2 is applied to the drug foil substrate (205) during t_heat2, or ■ The aforementioned t_wait2 and t_heat2 are distributed in alternating sections; B. using a temperature sensor to determine the temperature (T_meas) of the drug foil substrate during t_meas2; C. If T_meas ≤ T_exp, then t_heat2 = 1% to 100% of (t_period2 - t_meas2), and t_wait2 = t_period2 - t_meas2 - t_heat2, otherwise t_heat2 = 0% to 100% of (t_period2 - t_meas2), and t_wait2 = t_period2 - t_meas2 - t_heat2, where T_exp is based on TP2; and D. Repeat steps A) to D) to match TP2 until tTTP2 is reached and / or HtTP2 has passed; in ■The control cycle time t_period2 ranges from 0.5ms to 5ms, ■The measurement time t_meas2 ranges from 1% to 40% of t_period2, ■t_period2=t_heat2+t_wait2+t_meas2, ■ t_period2 is the length of time for each cycle of measuring temperature and optionally heating the drug foil substrate (205), ■t_heat2 is the time for heating the drug foil substrate (205) within each t_period2, ■t_wait2 is the time during which the drug foil substrate (205) is not heated within each t_period2, t_meas2 is the time at which the temperature of the drug foil substrate (205) is measured within each t_period2, and ■The current ITP2 ranges from 10A to 50A.

3. The method according to any of the preceding claims, wherein t_period1 and / or t_period2 ranges from 0.55 ms to 4.0 ms.

4. The method according to any of the preceding claims, wherein t_meas1 and / or t_meas2 ranges from 5% to 35% of t_period1.

5. A method according to any one of the preceding claims, wherein ITP1 ranges from 50A to 290A.

6. The method according to any one of the preceding claims, wherein when T_meas is higher than tTTP1–50°C and lower than tTTP1–20°C, then c) is: if T_meas≤T_exp, then t_heat1=70% to 90% of (t_period1-t_meas1), and t_wait1=t_period1-t_meas1-t_heat1, otherwise, t_heat1=0% of (t_period1-t_meas1), and t_wait1=t_period1-t_meas1-t_heat1.

7. A method according to any one of the preceding claims, wherein when T_meas is above tTTP1–20°C, then c) is: if T_meas≤T_exp, then t_heat1=40% to 60% of (t_period1-t_meas1), and t_wait1=t_period1-t_meas1-t_heat1, otherwise, t_heat1=0% of (t_period1-t_meas1), and t_wait1=t_period1-t_meas1-t_heat1.

8. The method according to any one of the preceding claims, when T_meas is below tTTP1-50°C, step c) is.

9. If T_meas≤T_exp, t_heat1=2% to 100% of (t_period1-t_meas1), and t_wait1=t_period1-t_meas1-t_heat1, otherwise, t_heat1=0% to 80% of (t_period1-t_meas1), and t_wait1=t_period1-t_meas1-t_heat1.

10. The method according to any one of claims 2 to 8, wherein ITP2 ranges from 12A to 45A.

11. The method according to any one of claims 2 to 9, wherein step C) is.

12. If T_meas≤T_exp, t_heat2=2% to 80% of (t_period2-t_meas2), and t_wait2=t_period2-t_meas2-t_heat2, otherwise, t_heat2=0% to 80% of (t_period2-t_meas2), and t_wait2=t_period2-t_meas2-t_heat2.

13. The method according to any of the preceding claims, wherein the temperature sensor measures the resistance on the drug foil substrate (205), T_meas is measured by applying a measurement current I_meas to the drug foil substrate (205), and I_meas ranges from 0.1A to 20A.

14. The method according to any one of the preceding claims, wherein the predetermined temperature and resistance relationship of the drug foil substrate (205) is stored in a memory (230) of the disposable cartridge (200).

15. A disposable cartridge (200) configured to perform the method of any of the preceding claims and adapted to be connected to a handheld controller (100) implementing claim 14, the disposable cartridge (200) include: ■ an air inlet (220) located at one end of the airway (203); ■ an air outlet (202) at the other end of the airway (203), which is configured as a suction nozzle; ■ a drug foil substrate (205) with a water-impermeable surface, with or without perforations, placed within the airway (203); ■ a drug foil substrate support (204); ■ a solid drug film (207) coated on the drug foil substrate (205); and ■ An electrical connection (302) and / or a data connection (301) between the disposable cartridge (200) and the handheld controller (100) of claim 14.

16. A handheld controller (100) configured to perform the method of any one of claims 1 to 12 and adapted to be connected to the disposable cartridge (200) of claim 13, the handheld controller (100) include: ■ at least one battery (101), ■ at least one microcontroller (102); and ■ An electrical connection (302) and / or a data connection (301) between at least one battery (101), at least one microcontroller (102) and the disposable cartridge (200) according to claim 13.

17. The method of any one of claims 1 to 12, the handheld controller (100) of claim 14, or the disposable cartridge (200) of claim 13 for use in a condition or episode, wherein the drug in the solid drug film (207) is selected from: A. loxapine or a pharmaceutically acceptable salt thereof, wherein the condition or episode is agitation, include: i. Rapid control of mild to moderate agitation in adults with schizophrenia or bipolar disorder, or ii. Acute agitation associated with schizophrenia or bipolar disorder; B. alprazolam, estazolam or a pharmaceutically acceptable salt thereof, wherein the condition or seizure is epilepsy, wherein epilepsy comprises an epileptic seizure; C. fentanyl or a pharmaceutically acceptable salt thereof, wherein the condition or onset is breakthrough pain; D. Zaleplon, Amorant or a pharmaceutically acceptable salt thereof, wherein the condition or episode is a sleep disorder, including: i. Waking up in the middle of the night, or ii. Insomnia in the middle of the night; E. apomorphine, pergolide, ropinirole, pramipexole or a pharmaceutically acceptable salt thereof, wherein the disease or attack is Parkinson's disease, non-attack period of Parkinson's disease and / or idiopathic Parkinson's disease; F. Granisetron, ondansetron, palonosetron or a pharmaceutically acceptable salt thereof, wherein the condition or episode is: i. Nausea, ii. Vomiting, or iii. Cyclic vomiting syndrome; G. Nicotine or a pharmaceutically acceptable salt thereof, including nicotine meta-salicylate, wherein the condition or episode is nicotine addiction and / or smoking cessation; or H. Ropinirole, pramipexole or rotigotine, wherein the condition or episode is restless legs syndrome.

18. A medicament for use in the method of any one of claims 1 to 12, the handheld controller (100) of claim 14, or the disposable cartridge (200) of claim 13, the medicament comprising a drug selected from the group consisting of loxapine, alprazolam, estazolam, fentanyl, zaleplon, amorant, apomorphine, pergolide, ropinirole, pramipexole, granisetron, ondansetron, palonosetron, nicotine, nicotine meta-salicylate, rotigotine, or a pharmaceutically acceptable salt thereof.

19. A drug deposited on a drug foil substrate (205) for a condition or attack, the drug foil substrate (205) being the drug foil substrate (205) of the method of any one of claims 1 to 12, the handheld controller (100) of claim 14, or the disposable cartridge (200) of claim 13, wherein when the drug is: A. loxapine or a pharmaceutically acceptable salt thereof, wherein the condition or episode is agitation, include: i. Rapid control of mild to moderate agitation in adults with schizophrenia or bipolar disorder, or ii. Acute agitation associated with schizophrenia or bipolar disorder; B. alprazolam, estazolam or a pharmaceutically acceptable salt thereof, wherein the condition or seizure is epilepsy, wherein epilepsy comprises an epileptic seizure; C. fentanyl or a pharmaceutically acceptable salt thereof, wherein the condition or onset is breakthrough pain; D. Zaleplon, Amorant or a pharmaceutically acceptable salt thereof, wherein the condition or episode is a sleep disorder, including: i. Waking up in the middle of the night, or ii. Insomnia in the middle of the night; E. apomorphine, pergolide, ropinirole, pramipexole or a pharmaceutically acceptable salt thereof, wherein the disease or attack is Parkinson's disease, non-attack period of Parkinson's disease and / or idiopathic Parkinson's disease; F. Granisetron, ondansetron, palonosetron or a pharmaceutically acceptable salt thereof, wherein the condition or episode is: i. Nausea, ii. Vomiting, or iii. Cyclic vomiting syndrome; G. Nicotine or a pharmaceutically acceptable salt thereof, including nicotine meta-salicylate, wherein the condition or episode is nicotine addiction and / or smoking cessation; or H. Ropinirole, pramipexole or rotigotine, wherein the condition or episode is restless legs syndrome.

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