ES2360634T3 - VARIABLE DOSE INHALATION DEVICE. - Google Patents

Abstract

Device (10) for inhaling dry powder to distribute a therapeutic agent to a patient, in which the therapeutic agent is a dry powder (P) that is disaggregated by a vibrator and captured in a stream of air (F) to be distributed to the patient. patient, in which the inhalation device (10) comprises at least two vibrators (36, 37) to selectively engage with two or several dose containers, characterized in that the two or more dose containers contain dose amounts same or different units of said therapeutic agent, dose packages which are combined to compose a desired dose of said therapeutic agent.

Description

The present invention relates generally to the field of inhalation devices. The present invention has utility in particular in inhalation devices that use vibrations to facilitate the suspension of drugs or therapeutic agents, either in powder form or in liquid form in an inhaled gas stream (for example, inhaled air), and will describe in relation to said utility, although other utilities are contemplated.

It is known that certain respiratory diseases respond to treatment through the direct application of drugs or therapeutic agents. Since these agents or drugs are available very easily in the form of dry powder, the most practical way to achieve their application is by inhaling the powder material through the nose or mouth. This powder form results in a better use of the agent or drug, because the agent or drug is deposited exactly in the desired place and where its action may be necessary; therefore, often minimal doses of the agent or drug are as effective as larger doses administered by other means, with a subsequent notable reduction in the incidence of unwanted side effects including risks of infra or overdose and costs. Alternatively, this form of the agent or drug can be used for the treatment of diseases other than those of the respiratory system. When agent 15 or drug is deposited in very large surface areas of the lungs, it can be absorbed very quickly into the bloodstream; therefore, this method of application can replace administration by injection, tablets or other conventional means.

The opinion of the pharmaceutical industry is that the biological availability of most drugs is optimal when the drug particles distributed to the respiratory tract are between 1 and 5 microns in size. 20 However, the distribution of drug particles in this size range presents several problems:

(1) Small-sized particles develop an electrostatic charge during manufacturing and storage. This causes the particles to agglomerate or aggregate, which results in groups of particles having an effective size greater than about 5 microns. Therefore, the probability that these large groups reach the deep part of the lung is reduced. In turn, this results in a lower percentage of the drug available for absorption by the patient.

(2) The amount of active drug that needs to be distributed to the patient can be of the order of only a few (for example, 10) micrograms. For example, for albuterol, in the case of a drug used for asthma, it is usually 25 to 50 micrograms. Current manufacturing equipment can effectively distribute aliquots of drugs in doses of the milligram range with acceptable accuracy. Therefore, the standard practice is to mix the active drug with an excipient filler or a filler such as lactose. This additive also makes the drug "easy to flow." This filler is also called a carrier since the drug particles also adhere to those particles through electrostatic or chemical bonds. These carrier particles are much larger in size than the drug particles. The ability of the dry powder inhaler to separate the drug from the carrier is an important characteristic parameter in the effectiveness of the design.

(3) The active drug particles with sizes larger than about 5 microns will be deposited in the mouth or throat. This introduces another level of uncertainty since the biological availability and absorption of the drug in these locations is different from those in the lungs. Dry powder inhalers need to minimize the drug deposited in these locations to reduce the uncertainty associated with the biological availability of the drug.

Dry powder inhalers (DPIs) of the prior art usually have a means of introducing the drug (carrier plus active drug) into a high velocity air stream. The high velocity air stream is used as the main mechanism to break the group of powdered particles or separate the drug particles from the carrier. Several prior inhalation devices useful for distributing this powdered form of the medicament are known in the prior art. For example, in U.S. Pat. Nos. 3 507 277, 3 518 992, 3 635 219, 3 795 244 and 3 807 400, inhalation devices are disclosed with means for piercing a capsule containing a powdered medicine, which after inhalation is extracted from the perforated capsule and inserted into the user's mouth. Some of these patents disclose helix means, which after inhalation help distribute the powder outside the capsule, so that it is not necessary to rely exclusively on the air inhaled to aspirate the powder from the capsule. For example, in US Pat. No. 2 517 482, a device is disclosed with a powder-containing capsule located in a lower chamber before inhalation, where it is pierced by manual depression of a drilling pin by the user. After the perforation, the inhalation is initiated and the capsule is attracted to an upper chamber of the device where it moves in all directions to cause the distribution of the dust through the perforated holes and into the stream of inhaled air. U.S. Pat. No. 3 831 606 discloses an inhalation device with multiple piercing pins, propeller means, and a self-contained power source for operating the

propeller means through an external manual manipulation, so that after inhalation the propeller means helps distribute the powder to the flow of inhaled air. See also US Pat. 5 458 135.

The prior description of the prior art is taken largely from US Pat. No. 3 948 264, by Wilke et al., who disclose a device to facilitate the inhalation of a powder medication comprising a body part with main and secondary input channels and with an output channel. The secondary inlet channel provides a closure for a capsule containing the powder medication, and the outlet channel is formed as a mouthpiece, which protrudes from the body. A capsule piercing structure is provided, which after one rotation makes one or more holes in the capsule so that after vibration of the capsule by an electromechanical vibrator, the powdered drug can be released from the capsule. The drilling means disclosed in the document by Wilke et al., Comprises three radially mounted, spring-forced drilling needles, mounted in a trocoidal chamber. After manual rotation of the chamber, the simultaneous inward radial movement of the needles pierces the capsule. Subsequent rotation of the chamber allows the needles to be retracted by their spring mounts to their original positions to remove the needles from the capsule. At its innermost end, the electromechanical vibrator comprises a vibrating piston rod that projects at the intersection of the input channel and the output channel. Connected to the piston rod 15 is a mechanical solenoid buzzer to drive the rod to vibrate. The buzzer is equipped with a high energy electric battery and is activated by an external button. According to Wilke et al., After inhalation through an output channel and the simultaneous pressing of a switch to activate the electromagnetic vibration medium, air is aspirated through one or more input channels and the air stream Through a secondary inlet channel, the capsule is raised against a vibrating piston rod. In this way, the capsule is rapidly vibrated with the powder being fluidized and distributed from the holes drilled therein. This technique is normally used in manufacturing, to distribute dust through a hopper, where the hopper is vibrated to fluidize the powder and move it through the hopper outlet. The holes drilled in the capsule represent the hopper outlet. The flow of air through the inlet channel helps to remove dust from the capsule and transports this powder through the outlet channel to the user's mouth. Wilke et al. They further disclose that the electromechanical vibrator means can be located at a right angle to the inlet chamber, and that the amplitude and frequency of the vibration can be modified to regulate the distribution characteristics of the inhaler.

The vibrator in the inhaler of Wilke et al. disclosed, it is an electromechanical device consisting of a rod driven by a solenoid buzzer. According to Wilke et al., This electromechanical means can be a motor that drives a cam. A drawback of the implementation of the inhaler disclosed by Wilke is the relatively large mechanical movement required for the bar to effectively vibrate the capsule. The large movement of the bar, usually hundreds of microns, is necessary due to the elasticity of the capsule walls and the inertia of the drug and the capsule.

Solenoid buzzers usually have operating frequencies less than five kHz. This operating frequency tends to be noisy, and therefore from the patient's point of view is not desirable when incorporated into a dry powder inhaler. Another drawback of Wilke's electromechanical actuators is the need for a high energy source, therefore requiring a large battery source or frequent battery pack changes for portable units. These two characteristics are not desirable from the point of view of safety and the "ease of use" of the patient. 40

The inhaler of Wilke et al. It is primarily designed to reduce the amount of dust left in the capsule, in relation to other inhalers cited in the patent description. However, Wilke et al. they do not address the need to disaggregate the powder into particle sizes or groups of less than 6 microns in size as required to effectively distribute the medication to the lungs; on the contrary, the inhalers of Wilke et al., such as those of the prior art, continue to depend on the speed of the air stream to disaggregate the dust released into the air stream, in particle sizes suitable for distribution to lungs.

In US Pat. No. 5,284,133, from Bums et al., another prior art inhalation device is disclosed. In this device, a liquid medication is atomized by an ultrasonic device such as a piezoelectric element. Next, a stream of air, usually at high speed, or a propellant transport the atomized particles to the patient. However, the energy required to atomize the liquid medication 50 in the nebulizer is prohibitively high, making this approach to the distribution of medications to the lungs essentially viable only as a desktop unit.

Therefore, prior art devices have a number of disadvantages, which include:

• The performance of prior art inhalers depends on the flow generated by the user. A lower flow rate may result in the powder not being fully disaggregated, and therefore negatively affects the dose distributed to the patient.

• Inconsistency in the biological availability of drugs between one dose and another, due to the lack of consistency in the disaggregation process.

• Great energy requirements to boost inhalers with electromechanical base, which increases the size of the devices.

Another disadvantage of prior art devices is the ability to distribute only a fixed dose of 5 medication to the patient, while the needs of the patients regarding the dosage of the medication may vary depending on the current state of the patient's medical condition. . For example, a diabetic patient may need different amounts of insulin based on the measurement of the patient's blood glucose concentration.

In the U.S. document 5 694 920, published on December 9, 1997, an inhaler is used that uses vibration to facilitate the suspension of dust in a gas, which overcomes the above-mentioned disadvantages and disadvantages and others of the prior art. More specifically, the inhaler of our mentioned patent comprises a piezoelectric vibrator to vibrate the powder. A controller is disclosed to control the supply (i.e., the amplitude and / or frequency) of the drive electricity to the vibrator, to cause vibration of the powder that is adapted to optimally suspend at least a part of the dust in the gas. 15 As described in our aforementioned patent, the controller may comprise a user-operated control to allow the user to select the frequencies and / or amplitudes of vibration in order to optimally suspend the type of dust being used in the gas currently in the inhaler. The user-operated control is pre-calibrated with the controller to cause the controller to adjust the frequency and / or the amplitude of the drive electricity supplied to the vibrator, to that necessary to vibrate the type of powder 20 selected by the control user-operable, so that it optimally suspends at least part of the dust in the gas. The user-operated control may comprise gradations of selection in terms of the average size of the dust particles to be suspended in the gas, and / or in terms of the frequencies and amplitudes of vibration desired. The vibration frequency would be adjusted, at least, to about 12 kHz, to optimally suspend said normally used powder medications in the gas. Of course, the frequency and amplitude of vibration can be adjusted to optimize the suspension of the powder medication being used.

An electrostatic field is established through the air stream, so that by controlling the intensity of the electrostatic field, only the particle sizes of interest are introduced into the air stream, while larger particles are left in the container . This reduces the inconsistency associated with the biological availability of the drug due to the large particles that are deposited in the mouth or throat, as is usual with the devices described in the prior art.

WO 02/04055 A1 and U.S. 2002/0129812 A1 disclose fogging devices for the distribution of therapeutic agents that are fluid. The compartments of fluid therapeutic agents are accessed repeatedly, in particular each time a certain amount of agent is to be inhaled. Therefore, there is a risk of exposure to oxygen and / or moisture, inherent in this class of inhalation devices.

WO 99/64095 A2 discloses an inhalation device that requires electronic circuits to electronically control the dosage.

EP 1 166 812 A1 discloses a blister pack for use with inhalation devices.

The U.S. document 6 142 146, published on November 7, 2000, discloses an inhaler with piezoelectric elements 40 that are designed to vibrate at different amplitudes and frequencies, such that, for example, two different medications can be advantageously dispersed from the same inhaler, without compromising the performance of any of the medications. This allows the distribution of two drugs that, although they act together, it may not be easy to store together. For example, an asthma inhaler containing a bronchodilator, such as albuterol, and a steroid that may require different piezoelectric configurations may be provided.

Similarly, US Pat. No. 6 684 879 published on February 3, 2004, by Coffee et al., shows an inhaler that uses two or more piezoelectric resonators arranged to resonate at different frequencies in order to aerosolize liquid droplets.

The present invention discloses an improvement over prior art inhalation devices, such as our aforementioned US Pat. No. 6 142 146. This invention allows the user to easily administer variable doses of a drug or therapeutic agent. As used herein, the terms "medication", "therapeutic agent", "agent" and "drug" are used interchangeably. The prior art inhalers allowed the user to only administer a single, or a number

Extremely limited dose at a time. The objective of the present invention is to allow the user to administer variable doses of one or more drugs or therapeutic agents in a single inhalation or in a controlled number of inhalations. Another object of the invention is to limit the number of inhalations necessary to administer a desired amount of a medication or a combination of different medications, and therefore improve compatibility and efficacy. 5

This objective is achieved by the inhalation devices of claim 1.

For example, in the case of the distribution of powdered insulin in an inhaler, the inhalers currently available for the distribution of powdered insulin are all single-dose devices. However, a person with diabetes may need varying doses of insulin, multiple times during a day, depending on a measurement of their blood sugar level each time. This means that the user must transport 10 different inhalation devices that distribute each different dose, or the patient must take several aspirations in succession to achieve a desired dose. The inhaler of the present invention discloses an efficient and convenient way of providing variable doses of insulin in a single inhalation stage.

In one embodiment, the invention discloses an inhaler with two (or several) vibrating mechanisms or usable piezoelectric elements. Therefore, in the inhaler of the present invention, individual, quick-acting individual 15 ampoule containers of different doses can be inserted into the inhaler to provide the necessary dose. For example, if the user needs 8 units of insulin, a blister pack with 5 units and a blister pack with 3 units in the inhaler could be loaded, and distributed in a single shot. Therefore, the inhaler of the present invention discloses the simple and effective administration of varying amounts of a medication without the multiple inhalations required by prior art inhalers. twenty

In another embodiment of the invention, the inhaler contains two or several vibrating mechanisms or piezoelectric elements each located in different dust distribution chambers. The structure of the inhaler allows the user to insert individual blister packs of a drug, which may contain the same or different doses of medication, into the inhaler for single shot distribution. In a second embodiment of the inhaler, the two or several vibrating mechanisms or electrical elements are located in the same dust distribution chamber.

In another embodiment of the invention, two (or several) cartridge strips are inserted into the back of the inhaler. Each strip contains one or more blister packs that contain a drug or medicine. The user selects the desired dose of the medicine or drug, accessing one or a series of blister packs in one or both (or more) cartridge stages. 30

In another embodiment of the invention, individual blister packs of a drug or medicine are inserted using a mechanism or tool that allows the selection and manipulation of blister packs without finger contact.

In another embodiment of the invention, the blister packs are packaged in a spinning reel or cartridge and dropped, or placed one by one, in the inhaler. 35

In another embodiment of the invention (illustrated in Figure 13), multiple blister packs or metallized paper bags containing a drug, being opened or perforated and exposed to a resonant cavity can be activated simultaneously by a single vibrating mechanism or piezoelectric element. at the same time before the administration of the drug, thereby allowing the distribution of a variable dose of the drug by means of the expulsion of the drug from the resonant cavity, for example by means of a synthetic injector jet according to the 40 explanations of US 2005 / 0183724- A1.

In another embodiment of the invention (illustrated in Figure 14), a variable dose of a medicament is distributed to a patient using at least one vibrating mechanism or a piezoelectric element, which is used to simultaneously activate multiple or sequentially multiple dose packages selected to result in the distribution of a specific dose of the drug in an inhalation, where the dose can be varied according to the needs of the patient. In this embodiment, a combination of several smaller dose packages results in a total controlled dose that meets the needs of a patient. The dose containers are preferably blister packages or metallized paper bags. According to this embodiment of the invention, the dose containers comprise multiple small cavities or blister micro-containers on a metallized paper or inside a blister package that is continuously or intermittently displaced during the single inhalation / administration of the drug, passing on the vibrator or piezoelectric element or other mechanical actuator, wherein the variable dose distributed to the patient in an inhalation is defined by the number of small cavities or micro-blister packs that are open or perforated and administered to the patient during the inhalation. In one embodiment, each micro-ampoule may contain the same amount of drug, for example,

0.5 mg of the drug. For distribution to the patient of 1 mg of the drug, 2 micro-ampoules are opened or perforated. Similarly, for the distribution of 2 mg of the drug, 4 micro-ampoules are opened or perforated.

In another embodiment of the invention (illustrated in Figure 15), a variable dose of a drug is distributed to a patient using at least one vibrating mechanism or piezoelectric element, which is used to simultaneously activate one or more dose containers. . The number of activated dose packages will determine the total dose distributed to the patient.

In another embodiment of the invention (illustrated in Figure 16), a detector is arranged to monitor the amount of drug distributed when it is being administered from one or more dose containers containing a quantity of drug that exceeds the amount the patient needs. . Next, the detector stops the distribution of the drug once the necessary dose has been distributed to the patient, and the remaining drug is discarded or retained for future administration. Preferably, the detector is an optical or acoustic detector that can detect and quantify aerosol particles that travel through the flow channel of the inhalation device. In another embodiment, the detector is a detector that detects the amount of drug remaining in the blister pack or in the pack or in the dose packs, wherein the detector is preferably a piezoelectric detector or quartz microbalance detector, or an acoustic detector In one embodiment, the piezoelectric element 15 that is used to activate and vibrate the drug is also used as a detector to detect the amount of drug remaining in the vial or in the dose container, measuring the resonant frequency of the dose container or of the blister pack, or the electromechanical parameters of the piezoelectric actuator, such as the admittance of the piezoelectric actuator. In one embodiment, an acoustic detector is used to detect acoustic properties of the vial or to measure the resonant sonic waves generated in the vial and thereby monitor the amount of drug that remains in the vial. Once the detector has detected that the required amount of the drug has been distributed to the patient, measuring the amount of drug remaining or quantifying the aerosol particles that travel through the flow channel, the detector sends a signal to the control circuit to stop the distribution of drug to the patient. In another embodiment, the detector optically detects the amount of the drug remaining in the dose container or in the vial, by measuring the optical transmission through the dose package or the vial.

In another embodiment of the invention (illustrated in Figure 17), a canister contains sufficient amounts of drug for more than one dosage of the drug. The canister has an outlet that communicates with a dosing plate which, in a preferred form, comprises a rotating disk with micro-dosing cavities of equal or variable sizes, and a first valve plate which, in a preferred form, comprises a First swivel cap 30 is located between the canister and the dosing plate to allow the selection of the number of cavities to be filled with drug, thereby allowing to select a variable dose of the drug. In said embodiment, the first valve plate allows to open a selected number of cavities to be filled with the drug from the canister. A second valve plate which, in a preferred form, comprises a second rotating disk, is located between the dosing plate and the resonant cavity of an inhaler from which drug distribution 35 is carried out using a vibrating mechanism or a piezoelectric element to aerosolize and distribute the drug. In use, the first valve plate opens to select a specific number of micro-cavities corresponding to the desired dose. Then, the selected cavities are filled from the boat. Next, the first valve plate is closed and the second valve plate is opened allowing the drug to be transferred to the resonant cavity for aerosolization and distribution to the patient by launching the drug from the resonant cavity, for example by means of a synthetic injector jet according to the explanations of US 2005/0183724-A1.

In another embodiment of the invention, the distributed dose is estimated from the time of distribution and an appropriate calibration curve, wherein the time of the vibration or the piezoelectric activation of the vial or the drug container is correlated with The distributed dose. In this last embodiment, the necessary dose is distributed by controlling the time of distribution of the drug, or more specifically by controlling the time or duty cycle of the activation of the vibrating mechanism or the piezoelectric element in contact with the drug container. In this embodiment, for a maximum dose the entire amount of the drug contained in an individual drug vial or container is distributed, or for a smaller dose of the drug a partial amount of the drug contained in an individual drug vial or container is distributed. By disconnecting the vibrating element before the full dose contained in an individual drug container has been distributed, a variable dose of the drug can be distributed to a patient. Alternatively, a variable dose of the drug can be distributed to a patient by operating the vibrating element with a lower energy input, which results in a lower vibratory activation, or by operating the vibrating element with a smaller duty cycle, connecting and disconnecting intermittently the vibratory output. 55

Other methods, devices, features and advantages of the present invention will be seen from the following drawings and detailed description. It is understood that all such additional methods, devices, features and advantages that are included within this description, are within the scope of the present invention, and are protected by the appended claims.

Referring to the following drawings, many aspects of the invention can be better understood. The components of the drawings are not necessarily to scale, with the emphasis on clearly illustrating the principles of the present invention. In the drawings, equal reference numbers designate corresponding parts through all the various views, in which:

Figure 1 is a schematic view in longitudinal cross-section of a first embodiment of the inhaler manufactured in accordance with the present invention;

Figure 2 is a perspective view of the inhaler of Figure 1;

Figure 3 is a top perspective view of a drug or pharmaceutical ampoule cartridge or container, used in the first embodiment;

Figure 4 is a view similar to Figure 1, of a second embodiment of the invention. 10

Figure 5 is a top plan perspective view of the second embodiment of the invention;

Figure 6 is a schematic view in longitudinal cross section of the second embodiment of the invention;

Figure 7 is a top perspective view of the third embodiment of the invention;

Figure 8 is a top perspective view of the cartridge strips used in the third embodiment 15 of the invention of Figure 7;

Figure 9 is a top perspective view of the fourth embodiment of the invention;

Figure 10 is another top perspective view of the fourth embodiment of the invention of Figure 9;

Figure 11 is a top perspective view of the launcher and secondary storage device used in the fourth embodiment of the invention of Figures 9 and 10; twenty

Figure 12 is a top perspective view of the fifth embodiment of the invention and the reel used with the inhaler; Y

Figures 13 to 17 illustrate alternative embodiments of the invention.

Figures 1 to 3 illustrate a first embodiment of the present invention. An inhaler 10 includes a metal or hard plastic housing 18, with an L-shaped longitudinal cross-section in general, with a cap 11 of the mouthpiece. Housing 18 includes four airflow openings 20, 28, 30 and 32. The inhaler 10 includes a main air flow conduit 26, which extends along the length of the housing 18 from the front part 22 (in the opening 20) to the rear part 24 thereof (in the opening 28) and It has a square cross section in general, to allow air flow through it (indicated by arrow F in Figure 3).

The optional secondary air duct 31 is generally L-shaped and runs longitudinally from the opening 30 on the surface of the rear 24 of the housing 18 to the main duct 26. A unidirectional flow valve 50 is mounted on the inner surface of the main duct 26 through a spring-forced hinge mechanism (not shown), which is adapted to cause the valve 50 to completely block the flow S of air through the duct 31 to the main duct 26, when the pressure of the air flow F in the main duct 26 is below a predetermined threshold indicative of inhalation through the duct 26 35 by a user.

Two powder distribution chambers 54, 55 are formed in the housing 18 to contain powder medication cartridges 34, 35 to be inhaled. The housing 18 comprises a movable panel portion 75 articulated in the rear 24 to allow the blister packs or cartridges 34, 35 containing a drug or pharmaceutical product to be introduced into the two chambers 54, 55 and located in the seats 52 of the vibration mechanisms 36, 37, respectively between the four guiding means 60A, 60B, 60C, 60D such that the cartridges 34, 35 are mechanically coupled to the cartridges 34, 35 to allow the maximum to be transmitted Vibratory energy from the vibration mechanisms 36, 37 to the cartridges 34, 35. The guiding means 60A, 60B, 60C, 60D are designed to allow easy insertion by hand of the cartridges 34, 35 from any secondary packaging (not shown). ) and the capsule retention in the seats 52 in the two chambers 54, 55. 45 Preferably, the cap 11 of the nozzle is coupled to the panel 75 in an articulated rotating manner.

Also, the inhaler 10 preferably comprises a conventional miniature detector 40 of the pressure or velocity of the air stream, mounted on the inner surface of the duct 16 to detect the velocity and / or the pressure of the air stream F. Preferably, the detector 40 comprises a spring-loaded elastic flap limit switch, which generates electronic signals indicative of the speed and / or the pressure of the air flow F in the conduit 26, and transmits said signals to control the activation of the mechanism. vibrator based on 5 such signals. Alternatively, the detector 40 may comprise a pressure detector or an acoustic detector and a control as described in US Pat. No. 6 152 130 assigned to Microdose Technologies, Inc.

Preferably, the control circuit 48 is made as an application specific integrated circuit chip and / or as some other type of highly integrated circuit chip. Alternatively, the control circuit 48 may take the form of a microprocessor, or discrete electrical and electronic components. 10

The vibration mechanisms 36, 37 are preferably piezoelectric elements, formed of a material having a high resonant, preferably ultrasonic, vibratory frequency (for example, approximately 10 kHz to 100 MHz) and are made to vibrate with a frequency and amplitude concrete depending on the frequency and / or amplitude of the excitation electricity applied to the piezoelectric elements 36, 37. Examples of materials that can be used to constitute the piezoelectric elements 36, 37 include quartz and 15 polycrystalline ceramic materials (for example, titanate of barium and lead circotitanate). Advantageously, by vibrating the piezoelectric elements 36, 37 at ultrasonic frequencies, the noise associated with the vibration of the piezoelectric elements 36, 37 at lower frequencies (ie, non-ultrasonic) can be avoided.

In the present invention, an embodiment of the inhaler is also disclosed without the optional air duct 30 and without the air flow opening 30 and the valve 50. In this embodiment, the drug powder is discharged 20 directly to the main channel 26 of air flow.

In this first embodiment of the present invention, the drug is stored as unit doses in individual blister packs 34, 35. Specifically referring to Figure 3, the individual blister packs 34, 35 can contain two parts: a blister 90 and a substrate labeled 92. Blister 90 contains controlled doses or aliquots of a dry powder medication or a liquid drug. The substrate labeled 92 25 serves several purposes: it provides information on what type and quantity of drug or medication is in the vial; supports the blister; and provides a handle for easily loading the blister packs 34, 35 in the inhaler 10. A large number or other signs (in this case, the number "9iu") on the label 92, indicate the size of the dose contained in the blister container For example, the number "9iu" indicates that the vial contains 9 units of insulin. Dosage containers of another size, for example a 3-unit container, would allow the user to select a dose of 3, 6, 9 or 12 units in a single aspiration by selecting one or combining two blister packages. Similarly, blister packs containing 1, 2 and 4 units would allow the user to select a dose of 1, 2, 3, 4, 5, 6 and 8 units in a single aspiration by selecting one or combining two blister packs. Similarly, blister packs containing 3, 4 and 5 units would allow the user to select a dose of 3, 4, 5, 6, 7, 8, 9 or 10 units in a single aspiration by selecting 35 one or combining two blister packs. . The large numbering allows the user to easily calculate the desired combination of blister packs to be inserted into the inhaler. The blister packs 34, 35 may also contain an electronically or mechanically readable indicator or label; containing the label or indicator information about the contents of the vial. The inhaler may comprise a mechanism to read this information in order to verify that the user receives the correct dose of the correct drug. 40

A second preferred embodiment 100 of the present invention is shown in Figure 4. In this embodiment, the inhaler 100 contains only a powder distribution chamber 102. The chamber 102 contains two vibration mechanisms 104, 106, which allow two blister packs 34, 35 to be placed in the seat of the vibration mechanisms 104, 106. The air flow P comprising the drug from the cartridges 34, 35 flows through passage 108 through conduit 31 to main conduit 26. 45

Figures 5 and 6 show a third embodiment 202 of the present invention. In this embodiment, the inhaler is designed to accommodate a pair of cartridge strips of which only 214 is shown, which are inserted into a slot (not shown) on the back 204 of the inhaler 202. A cover 206 (shown capped) of the mouthpiece is swivel articulated on a mouthpiece (not shown) on the front of the inhaler. Each strip of cartridges carries a series of blister packs 34. Preferably, all blister packs 34 50 in a particular strip contain similar amounts of medication. The user controls the desired dose of the medicine or drug by loading two strips of cartridges with different blister packs into the inhaler, and sliding the buttons 212 on the top of the inhaler 202 to access one or more blister packs in Each strip and pierce them. Once the user has selected the desired dose and the blister packs 90 have been perforated, the piezoelectric vibrators disaggregate the medication. Preferably, a flow and feedback detector may be provided, such as a noise generator or one or more lamps 210, as described in the published US application. No. 2003/0041859-A1, to inform the user when the medicine has been properly inhaled and when the dose has been completed. Depending on the total dose required, the user may need to switch the cartridge strips and inhale again, or take inhalations

additional with the same cartridge. After the user has inhaled, the respective strips are advanced, for example as a film camera, beyond the ampoules used. Preferably, the cover 208 around the strips 214 is manufactured transparently to allow the user to observe when the strips 214 are empty.

Figure 6 shows a strip 214 of cartridges consistent with the third preferred embodiment of the present invention. The cartridge 214 consists of multiple cartridges 34 with labels or indexes printed on it.

A fourth embodiment of the present invention, shown in Figures 7 to 9, allows the user to select individual ampoules 90 or combinations thereof from a protective cartridge, and insert said one or two ampoules 90 depending on the dose of drug required. , in the receiving slots 312 in an inhaler 300 using a mechanism or a tool 314. As previously described, the inhaler may comprise a flow and feedback detector such as a noise generator or lights 310 to inform the user when the medicine has been inhaled correctly and when the dosage has been completed. Also, if the user is not inhaling correctly, the inhaler 300 may be programmed to stop the dosage until the user is inhaling correctly. The inhaler 300 may also be programmed to add the number of distributed ampoules and maintain a dynamic total of the duration of the dosing event, and display the total on an LCD 302 or the like.

In this embodiment, a secondary packaging device or protective cartridge 320 protects and stores the individual blisters 90 before use. The secondary packaging device 320 contains slots 322 to contain the blisters 90. The displacement of the blisters 90 from the secondary packaging device 320 to the inhaler 300 is achieved using a mechanism or a tool 314. The mechanism or tool 20 312 preferably comprises a pair of parallel rails 324 with a groove to easily capture the blisters 90. A protective shield 316 in the mechanism or tool 314 protects the vial 90 when it is being transported between the cartridge and the tool in use. The mechanism or tool 314 is inserted into the cartridge 320 through the slot 322 to grab a vial 34. Next, the user removes the mechanism or tool 314, moves it to an opening 312 of the inhaler 300 and inserts it into the same. The mechanism or tool 314 is left in position while the inhaler is used. The mechanism or tool 314 is then removed, taking the worn out vial with it. A feature and an advantage of using the mechanism or tool is that contamination or possible damage to the blister caused by contact with the fingers or the hand of the user can be avoided.

A fifth embodiment of the present invention uses a reel or a rotating carriage 402 to protect the blisters 30 90 before distribution, as illustrated in Figure 10. During use, the rotating carriage 402 is mounted in a slot 404 in the inhaler 400. The rotating carriage 402 is rotated to distribute a vial 90 to the opening 410. The ampoules 90 can fall from the slot 404 through the opening 410 to the inhaler, where they can be opened and processed as before. Each of the ampoules contained in the reel or spinning cart contains the same dose of the drug. Other packing structures and techniques to protect the blisters are illustrated in Figures 11 and 12.

Referring now to Figures 13A and 13B, an embodiment of the present invention comprises the resonant cavity 500 that can aerosolize and expel the drug substance from drug ejection openings 510, after activation by vibrator 530, such as a piezoelectric actuator or a transducer, which is coupled to the resonant cavity 500. A window 50 of distribution of ampoules or 40 dose containers is provided to deposit a variable amount of the drug substance in the resonant cavity 500. The blister tape 540 It is coupled by the belt advancement mechanism 560, and advanced before dosing to bring the ampoules or dose containers containing drug into contact with the distribution window 520. In this embodiment, a selected number of ampoules 550 are perforated or opened on a blister tape 540 to result in the distribution of a desired dose of the drug. In this embodiment, multiple dose containers 550 are activated by a vibrator 530, opening them and exposing them simultaneously to the resonant cavity 520 at the same time, before drug administration, thereby allowing the distribution of a variable dose of the drug by the resource of expelling the drug from the resonant cavity, for example by means of a jet of synthetic injector.

Referring now to Figure 14A, in another embodiment of the invention a variable dose of a drug is distributed to a patient 50 using at least one vibrator 690, such as a piezoelectric element, which simultaneously or sequentially activates multiple packages of selected 630 or 635 doses, which results in the distribution of a specific desired dose of the drug, preferably in an inhalation. The distributed dose can be varied according to the needs of the patient, by selecting one or more 630 or 635 dose containers. The 630 and 635 dose containers are arranged on a 600, 610 or 620 tape in one or several rows 55 as is illustrated in Figures 14B and 14C, and may be of varying shapes, such as round 630 dose containers or elongated 635 dose containers, as illustrated in Figure 14D. The 630 and 635 dose containers are preferably blister packages or similar compartments formed on the carrier belt 600, 610 or 620 that may contain a predetermined amount of drug. In one embodiment, the tape 600 is displaced to

through the surface of the vibrator 690 continuously or intermittently, the protective tape 680 being detached from the individual dose containers 630 by the detachment mechanism 680. The belt 600 is advanced from the reel 670 by the advancement mechanism 660 of tape. Arrow 650 indicates the direction of movement of the ejected and aerosolized drug after actuation of the vibrator 690. The dose of the drug distributed to the patient is controlled by the number of open dose containers 630 and in contact with the piezoelectric actuator during the event of drug distribution. According to this embodiment of the invention, the dose containers comprise multiple small cavities or micro-ampoules on a metallic tape or paper or inside a vial that is continuously or intermittently displaced during the sole inhalation / administration of the drug, passing on the vibrator or piezoelectric element or other mechanical actuator, wherein the variable dose distributed to the patient in an inhalation is defined by the number of small cavities 10 or micro-blister packs that are open or perforated and administered to the patient during inhalation . In one embodiment, each micro-vial or 630 dose container may contain the same amount of drug, for example, 0.5 mg of the drug. For distribution to the patient of 1 mg of the drug, 2 micro-ampoules are opened or perforated. Similarly, for the distribution of 2 mg of the drug, 4 micro-ampoules are opened or perforated. fifteen

Referring now to Figure 14E, an embodiment of the present invention is shown in which a selected number of dose containers or micro-ampoules 630 are opened by piercing the top cover of the dose container, thereby allowing expulsion of the drug after contact with vibrator 690 (drilling mechanism not shown). In this embodiment, a series of micro-ampoules or dose containers 690 are in contact with vibrator 690 during the dosing event. The expulsion of the drug occurs only 20 from the micro-ampoules or containers 690 of perforated or open doses, so that the selection of the number of packages 690 of doses or open perforated micro-ampoules defines the variable dose of the drug to be distributed to the patient . Arrow 650 indicates the direction of movement of the ejected and aerosolized drug after actuation of vibrator 690.

Referring now to Figures 15A and 15B, in another embodiment of the present invention, a variable dose of a drug is distributed to a patient using at least one vibrator 700, which is used to simultaneously activate one or more packages 710. of dose. The number of activated dose packages will determine the total dose distributed to the patient. Figure 15A illustrates the distribution of a large amount of drug from a series of perforated or open dose packages 710, showing aerosolization and expulsion of the drug by arrows 720. 30

Figure 15B illustrates the distribution of a small amount of the drug from a perforated or open dose container 710, the aerosolization and expulsion of the drug being schematically shown by arrow 720. In this embodiment, the variable dose of the drug is defined by the number of 710 ampoules or dose containers that are perforated or opened.

In another embodiment of the present invention shown in Figures 15C and 15D, the distribution of the variable dose 35 of the drug is carried out by selecting the number of individual dose packages or ampoules 710 that are perforated and opened, and are all coupled to the vibrator 700. Figure 15C illustrates a single dose container 710 and Figure 15D illustrates three individual dose packages 710, showing aerosolization and expulsion of the drug by arrows 720.

Figures 16A and 16B illustrate another embodiment of the present invention in which a sensor or detector 40 is arranged to monitor the amount of drug distributed. The drug is being expelled from one or more dose containers that contain an amount of the drug that exceeds the amount the patient needs. The distribution of the drug is stopped once the necessary dose has been distributed to the patient, and the remaining drug is discarded or retained for future administration, which results in the distribution of a variable dose of the drug. The distribution of the drug is stopped by discontinuously operating the vibrator, such as the piezoelectric vibrator, which provides vibratory energy to the vial or dose container. Preferably, the detector is an optical or acoustic detector that can detect and quantify aerosol particles that travel through the flow channel of the inhalation device.

As illustrated in Figures 16A and 16B, the aerosolized drug column 800, which can also be a drug mixed with excipients, is moving through the flow channel 810 of the inhaler as shown by arrows 804 and 802 Then referring to Figure 16A, the aerosol 800 passes through an optical, acoustic sensor or other physical sensor or detector that can measure the properties of the aerosol column 800 and deduct the amount of drug that has passed through the channel of flow 810. The optical or acoustic source 820 is shown installed in the flow channel 810, while an optical or acoustic detector 830, also installed in the flow channel 810, can detect the attenuation of the signal emitted by the source 820 due to the interaction with the aerosol 800. The attenuation of the signal, integrated in the time during which the aerosol passes through the flow channel 810, allows to deduce the amount of drug which has passed through the flow channel 810. After a predetermined dose has passed through the flow channel 810, the activation of the piezoelectric actuator (not shown) is stopped and therefore the distribution of the drug is interrupted. Therefore you can

distribute a variable dose of the drug. In another embodiment, instead of an optical or acoustic detector 830, a reflector (not shown) is installed, which may reflect an attenuated optical or acoustic signal back to an optical or acoustic source 820, which in this embodiment may also receive the reflected signal, as is known in the art. The attenuation of the signal, integrated in the time during which aerosol passes through channel 810, allows to deduce the amount of drug that has passed through the flow channel 810. 5

Next with reference to FIG. 16B, an optical source 850 is installed outside the flow channel 810, with an optical fiber guide or an optical fiber or an optical conduit 840 entering the flow channel 810. The optical signal that comes out of the optical fiber 840 is attenuated by the aerosol 800 and detected by the optical detector 860. The signal, integrated during the time in which the aerosol passes through the flow channel, allows to deduce the amount of the drug that has passed through of the flow channel 810. After a necessary dose of the drug has passed through the flow channel 10 810, the activation of the piezoelectric actuator (not shown) is stopped and therefore the distribution of the drug is interrupted. Therefore, a variable dose of the drug can be distributed.

Alternatively, the detector is a detector that detects the amount of drug left in the blister pack or in the pack or in the dose packs, where the detector is preferably a piezoelectric detector or a quartz microbalance detector, or a acoustic detector In one embodiment, the piezoelectric element that is used to activate and vibrate the vial for expulsion of the drug is also used as a detector to detect the amount of drug remaining in the vial or in the dose container, measuring the resonant frequency. or electromechanical parameters of the piezoelectric actuator, such as the admittance of the piezoelectric actuator. In another embodiment, an acoustic detector is used to detect acoustic properties of the blister or to measure the resonant sonic waves generated in the blister and thereby monitor the amount of drug that remains in the blister. In another embodiment, the detector optically detects the amount of the drug remaining in the dose pack or in the vial, by measuring the optical transmission through the dose pack or in the vial. Once the detector has detected that the required amount of the drug has been distributed to the patient, measuring the amount of drug remaining or quantifying the aerosol particles that travel through the flow channel, the detector sends a signal to the control circuit to stop the distribution of drug to the patient.

Next with reference to Figures 17A to 17F, in another embodiment of the invention, a canister 900 contains bulk quantities, ie multiple doses, of a drug. An optional hygroscopic element 920 may be included in the canister to absorb moisture and maintain an optimum humidity level inside the canister 900. Canister 900 has an outlet that communicates with a metering plate 930 which, in a preferred form, 30 comprises a rotating disk with micro-dosing cavities 960 of equal or variable sizes, and a first valve plate 940 which, in a preferred form, comprises a first rotating lid that is located between the canister and the dosing plate to allow the selection of the number of cavities to be filled with drug, thereby allowing to select a variable dose of the drug. In said embodiment, the first valve plate 940 allows to select a selected number of cavities to be filled with the drug from the canister 900. A second valve plate 950 which, in a preferred form, comprises a second rotating disk, is located between the dosing plate and the resonant cavity of an inhaler from which drug distribution is carried out using a vibrating mechanism or a piezoelectric element to aerosolize and distribute the drug. In use, the first valve plate 940 is opened to select a specific number of micro-cavities 960 corresponding to the desired dose. Next, the selected cavities are filled from the canister 900 as shown schematically by arrow 970. Next, the first valve plate 940 is closed and the second valve plate 950 is opened, allowing the drug to be transferred as shown schematically by arrow 980, to the resonant cavity (not shown) for aerosolization and distribution to the patient by expulsion of the drug from the resonant cavity, for example by means of a synthetic injector jet. Figures 17B through 17C show the dosing plate 930 closed, open for filling with powder 910, and open for discharge 45 of dust 910 respectively. Figures 17E and 17F are top plan views of the dosing plate 930 shown with the first valve plate 940 open to select a variable dose of drug powder 910 through the selection of a variable number of micro cavities 960 -dosage.

In another embodiment of the invention, an inhaler similar to the inhaler 10 shown in Figure 1 or to the inhaler 100 shown in Figure 4 is provided, but with only a vibration mechanism 36 or 37 or 104 or 106. The dose 50 distributed from a single cartridge 34 or 35 coupled with the vibration mechanism, is estimated from the distribution time and an appropriate calibration curve, wherein the vibration time or the piezoelectric drive of the cartridge 34 or 35 which can be a blister or A drug container is correlated with the distributed dose. In this last embodiment, the necessary dose is distributed by controlling the time of distribution of the drug, or more specifically by controlling the time or the utilization cycle of the activation of the vibrating mechanism or of the piezoelectric element in contact with the drug container. In this embodiment, the entire amount of the drug contained in an individual drug vial or container is distributed for a maximum dose, or a partial amount of the drug contained in an individual drug vial or container is distributed for a smaller dose of the drug. By disconnecting the vibrating element before the full dose contained in an individual drug container has been distributed, a variable dose of the drug can be distributed to a patient. 60 Alternatively, a variable dose of the drug can be distributed to a patient by operating the element

vibrating with a lower energy input, which results in a lower vibratory activation, or by operating the vibrating element with a smaller duty cycle, intermittently connecting and disconnecting the vibratory output.

The embodiments of the present invention described above are simply possible examples of implementations, set forth simply to facilitate a clear understanding of the principles of the invention. 5 Many variations and modifications can be made to the embodiment or embodiments of the invention described above, without substantially departing from the spirit and principles of the invention.

Claims (9)

1. Dry powder inhalation device (10) for distributing a therapeutic agent to a patient, in which the therapeutic agent is a dry powder (P) that is disaggregated by a vibrator and captured in a stream of air (F) a distribute to the patient, in which the inhalation device (10) comprises at least two vibrators (36, 37) to selectively engage with two or several dose containers, characterized in that the two or several 5 dose containers contain unit dose amounts of said therapeutic agent the same or different, dose packages which are combined to compose a desired dose of said therapeutic agent. 2. Inhalation device according to claim 1, characterized in that said at least two vibrators (36, 37) vibrate at the same frequency and / or amplitude. 3. Inhalation device according to claim 1, characterized in that said at least two vibrators (36, 37) vibrate at different frequencies and / or amplitudes. 4. Inhalation device according to claim 1, characterized in that said at least two vibrators (36, 37) comprise piezoelectric vibrators. 5. Inhalation device according to claim 1, characterized in that said at least two vibrators (36, 37) comprise electrostatically driven diaphragms. fifteen 6. Inhalation device according to claim 1, characterized in that said dose containers comprise blister packages (34, 35) containing measured amounts of said therapeutic agent. 7. Inhalation device according to claim 6, characterized in that a series of said blister packs (34, 35) are supported on a strip. 8. Inhalation device according to claim 1, characterized in that the dose containers comprise 20 dose sizes selected from the group consisting of 1, 2, 3, 4 and 5 unit doses. 9. Inhalation device according to claim 8, characterized in that the therapeutic agent comprises insulin, and the dose packages comprise 1 unit dose container of insulin, 2 unit dose containers of insulin, 3 unit dose packages of insulin, 4 containers of unit doses of insulin and 5 containers of unit doses of insulin. 25