RU2752613C1 - Method and apparatus for evaporation and inhalation of isolated substances - Google Patents

Abstract

FIELD: medical equipment.SUBSTANCE: invention relates to medical equipment, namely to a dosing element for application with an inhaler. The dosing element includes at least one biologically active substance released by evaporation. The dosing element is comprised of a plate containing a solid carrier material. The biologically active substance is located in the carrier material and/or on said material. The apparatus includes an air-permeable electrically resistive heating element in thermal contact with said plate. The carrier material is characterised by a sufficiently low electrical conductivity to avoid a current being passed through the material instead of said electrically resistive heating element. The carrier material is stable and inert at the evaporation temperature of the biologically active substance.EFFECT: technical result of the invention is controlled and reproducible delivery of a predetermined amount of an isolated vaporable biologically active substance by inhalation.23 cl, 15 dwg

Description

Related applications

This application claims priority under Provisional US Patent Application No. 62/019225 (patent attorney case number 59426), filed June 30, 2014; 62/035588 (patent attorney case number 59871), filed on August 11, 2014; 62/085772 (patent attorney case number 59424), filed December 1, 2014; 62/086208 (Patent Attorney File No. 61145), filed December 2, 2014, and 62/164710 (Patent Attorney File No. 60652), filed May 21, 2015, the entire contents of all are incorporated herein by reference, as if has been fully set out in this document.

Technology area

The present invention, according to some of its variants of implementation, relates to the field of pharmacology and, more specifically, but not exclusively, to methods and devices for controlled delivery by inhalation of volatiles.

State of the art

Over the years, many methods and devices have been developed to achieve effective delivery of a biologically active (pharmaceutically active) agent to a subject in need of pharmaceutical treatment. Oral ingestion, intravenous delivery and subcutaneous injection are the most common examples of modern delivery techniques. While these techniques are generally effective, they suffer from several pharmacokinetic limitations, which additionally often result in significant patient noncompliance. For example, the therapeutic benefits of traditional methods often wear off within hours of the initial dose, while the discomfort associated with injections often results in difficulty in administration and maintenance. Even oral administration may be ineffective in cases where the biologically active agent has poor bioavailability and in cases of subjects unable to swallow the biologically active agent due to nausea and / or vomiting.

One example of a highly effective biologically active agent is dronabinol, a pure THC isomer, or (-) - trans-Δ9-tetrahydrocannabinol, which is one of the main biologically active substances found in cannabis. Dronabinol is produced synthetically and sold under the trade name Marinol®, however, its use is very limited due to its inherent properties such as viscosity and hydrophobicity, which translate into pharmaceutically low bioavailability and uncontrolled efficacy when delivered by ingestion. For example, it takes more than one hour for Marinol® to achieve full systemic effect compared to a few seconds or minutes for smoked or vaporized cannabis. Some patients accustomed to inhaling enough cannabis smoke to manage symptoms have complained of too intense and untimely delayed intoxication from pre-determined doses of marinol. Many patients reported that marinol produces a more acute psychedelic effect than cannabis, and it has been suggested that this discrepancy may be explained by the difficulty in regulating the amount of biologically active agent in a subject at any given time, since this viscous hydrophobic agent after being absorbed through the gastrointestinal tract can be temporarily stored in adipose tissue until it reaches target receptors in the central nervous system.

While smoking is generally discouraged due to the negative effects of smoke inhalation and poor delivery efficiency of unburned biologically active agent, vaporization and inhalation of drug vapors suffering from low bioavailability may represent a viable solution to injection problems. and swallowing. A partial solution is provided by some vaporization methods aimed at delivering inhaled, volatile biologically active agents while avoiding the inhalation hazard of smoking. While the temperature in the center of the burning cigarette is 750-800 ° C, evaporation can be carried out at any given temperature, thereby allowing the vapors of the biologically active agent to form below the combustion temperature at which pyrolytic toxic compounds are formed. Evaporation methods have been shown to reduce the formation of carbon monoxide and highly carcinogenic compounds such as polycyclic aromatic hydrocarbons (PAHs), benzene and tar.

However, none of the currently known smokeless vaporization devices can be used to administer vaporizable biologically active agents under general pharmaceutical standards and practices due to the impossibility of accurate and reproducible control of the amount inhaled by the patient. Pulmonary delivery of volatile biologically active agents in the vapor phase varies within and between practically delivered doses due to the subjective visual assessment of the metered amount administered by the user, with repeated asynchronous inhalations from the same administered dose, inconsistent inhalation dynamics and time-dependent vapor condensation on the inner surface of the device. As a consequence, currently used vaporizers make correct pharmaceutical dosing and control of the medical regimen unrealistic or impractical.

International Patent Application Publication No. WO 2008/116165 discloses systems and methods for the pulmonary delivery of a drug to the respiratory system of a patient, wherein the drug is delivered in purified air at positive pressure with respect to atmospheric pressure, while the drug is available in a variety of forms, injected in a controlled manner into a stream of purified air in aerosol, nebulized or vaporous form.

US Patent Application Publication No. 20140238423 discloses an electronic smoking article that includes a liquid material and a heating wick configured to absorb liquid material and heat the liquid material to a temperature sufficient to vaporize the liquid material and form an aerosol. The wick heating element consists of two or more layers of electrically resistive mesh material. This device does not provide for the controllability and / or reproducibility of the amount delivered to the subject.

Rabinowitz J.D. et al. [J. Pharmacol. Exp.Ther., 2004, 309 (2), p. 769-75] investigated the systemic delivery of pure pharmaceutical compounds without degradation products through an appropriate process, which also includes inhalation of a thermally generated aerosol. According to Rabinowitz J.D. et al. the drug is applied in the form of a thin film on a metal heating element and evaporated by heating the element; the delicate nature of the drug coating minimizes the length of time that the drug is exposed to high temperatures, thereby preventing thermal degradation, and the vaporous drug rapidly condenses and coagulates into micron-sized aerosol particles.

In international patent application No. WO 2012/085919, which is incorporated into this description by reference, the present assignees describe, inter alia, devices for inhaling metered doses for controlled vaporization and pulmonary delivery of biologically active agents from plant material by applying heat, and the device is made with the ability to vaporize a precise amount of the plant material agent in a highly reproducible manner during airflow control to ensure complete pulmonary delivery of a predetermined dose.

Additional prior art includes WO 2008/024490 and WO 2008/024408, US Patent Nos. 6703418, 7169378, 7987846 and 8235037, and US Patent Application Publication Nos. 20140100249, 20120252885, 20100168228, 20080181942, 20080176885, 200800778382 , 20060258738 and 20060167084.

The essence of the invention

Provided herein is a dosage unit comprising at least one isolated biologically active agent applied to a carrier material in thermal contact with a heating element configured to vaporize a predetermined amount of a pulmonary delivery agent, as well as a vaporization and pulmonary delivery device. an isolated agent and methods for preparing a dosage unit, controlled release of an agent from it, methods for their pulmonary delivery and methods for treating pathological conditions amenable to treatment by pulmonary delivery of the isolated biologically active agent.

In accordance with an aspect of some embodiments of the present disclosure, a dosage unit is provided for pulmonary delivery of at least one biologically active agent to a user, which includes:

plate; as well as

an electrical resistive heating element in thermal contact with at least part of the plate surface or passing along it,

wherein at least one biologically active agent is included in the isolated biologically active agent, and the plate includes a solid carrier material and the biologically active agent is in and / or on the carrier material.

In accordance with some embodiments, the electrically resistive heating element extends across at least two opposite surfaces of the plate.

In accordance with some embodiments, the carrier material does not substantially react with the biologically active agent when in contact with the biologically active agent in a temperature range that ranges from storage temperature to the combustion / decomposition temperature of the biologically active agent.

In accordance with some embodiments, the carrier material does not substantially react with the biologically active agent when contacted with the biologically active agent at a temperature in the range from storage temperature to 50 ° C higher than the vaporizing temperature of the biologically active agent.

In accordance with some embodiments, the carrier material has a combustion and / or decomposition and / or melting temperature higher than the evaporation temperature of the biologically active agent.

In accordance with some embodiments, the carrier material has a combustion and / or decomposition and / or melting temperature that is higher than the evaporation temperature of the biologically active agent by at least 50 ° C.

In accordance with some embodiments, the carrier material has an electrical resistivity of at least 10 μΩ⋅hm.

In some embodiments, the carrier material has a thermal conductivity of at least 0.1 W / (m⋅K).

In some embodiments, the carrier material includes a material selected from the group consisting of glass, quartz, ceramic composite, silicon carbide, mullite, alumina, silicone, and polytetrafluoroethylene.

In accordance with some embodiments, the plate is characterized by an air-permeable structure that allows a flow of at least 0.5 liters of gas per minute at a vacuum of at least 1-5 kPa.

In some embodiments, the plate is a single breathable matrix.

In some embodiments, the plate is an air-permeable plurality of packaged particles.

In some embodiments, the particles have a diameter greater than 10 microns.

In some embodiments, the isolated biologically active agent is a liquid having a viscosity of at least 10 centipoise (cp).

In some embodiments, the boiling point of the recovered biologically active agent is greater than 80 ° C.

In some embodiments, the octanol-water partition coefficient (log P) of the isolated biologically active agent is greater than 5.

In some embodiments, the octanol-water partition coefficient (log P) of the isolated biologically active agent is greater than 1.

In accordance with some embodiments, the isolated biologically active agent includes a synthetic biologically active agent.

In some embodiments, the isolated biologically active agent comprises a pure plant extract.

In some embodiments, the biologically active agent is selected from the group consisting of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerols (CBG), cannabichromenes (CBC), cannabinol (CBN), cannabinodiol (CBDL), cannabicyclol (CBL) ), cannabielsoin (CBE), cannabidivarin (CBDV), tetrahydrocannabivarin (THCV), cannabitriol (CBT), terpene, flavonoid, and combinations thereof.

In some embodiments, the biologically active agent is selected from the group consisting of opium, salvinorin, cathinone, pucatein, thujone, damianin, bulbocapnin, cavalactone, lagochilin, lactucaria, glaucine, ergine, ibogaine, aporphine, leonurinuprenol atropine, , fentanyl, hydromorphone, methadone, midazolam, nalbuphine, naloxone, naltrexone, oxycodone, phenytoin, remifentanil, rizatriptan, sildenafil, sufentanil, and zolpidem.

In some embodiments, the biologically active agent is (-) - trans-Δ9-tetrahydrocannabinol (dronabinol).

In accordance with some embodiments, the biologically active agent is provided in and / or on the carrier material in a predetermined amount.

In some embodiments, the resistive heating element is a metal heating element.

In accordance with some embodiments, the resistance heating element includes a U-shape with two ends and an opening in which the plate is located such that an electric current flows through both of at least two opposite surfaces when a voltage is applied between the two ends.

In some embodiments, the resistive heating element is secured to the plate, keeping the plate on the metering unit.

In accordance with some embodiments, the resistance heating element comprises a portion packed and extending within the plate.

In accordance with some embodiments, the portion of the resistance heating element passing through the plate is an air-permeable resistance heating element.

In some embodiments, the breathable resistance heating element provides a flow of at least 0.5 liters of gas per minute at a vacuum of at least 1-5 kPa.

In some embodiments, the resistive heating element includes a resistive grid.

In some embodiments, the resistive heating element includes at least one etched metal foil strip.

In some embodiments, the etched metal foil tape is provided with a resin backing that includes a plurality of perforations to make it breathable.

In accordance with some embodiments, the etched metal foil tape includes an increased resistance tapered region that melts to break electrical continuity along the tape during electrical power dissipation occurring after the biologically active agent is released.

In accordance with some embodiments, the etched metal foil tape is attached to a fusible member configured to break electrical continuity along the tape during electrical power dissipation occurring after the biologically active agent is released.

In accordance with some embodiments, the dispensing unit includes a breathable support mesh, a separating plate, and a heating element, the supporting mesh being sufficiently closed to hold the plate within the dispensing unit.

In accordance with some embodiments, the breathable support mesh allows a flow of at least 0.5 liters of gas per minute at a vacuum of at least 1-5 kPa.

In accordance with some embodiments, the resistive heating element includes an electrode contact receiving region on either side of a region extending over the plate.

In accordance with some embodiments, the resistive heating element includes a transport arm lock region adapted to be attached to the transport arm of the dose withdrawal tool.

In accordance with some embodiments, the dosage unit comprises a plurality of heating element regions, each region individually configured to receive electrical current.

In some embodiments, heating elements are associated with a corresponding plurality of plates.

In accordance with some embodiments, the dispensing unit further includes a frame into the opening of which the plate is appropriately pressed.

In accordance with some embodiments, the frame is heat-resistant to at least the temperature at which the biologically active agent evaporates.

In some embodiments, the resistance heating element is in thermal contact with the plate and extends at least through the opening.

In some embodiments, the resistive heating element is partially embedded in a frame surrounding the edges of the opening.

In accordance with some embodiments, the frame includes an area away from the opening to which the resistance heating element is attached.

In accordance with some embodiments, the resistance heating element is attached to the region by at least partially melting the frame in the region such that the frame material flows into one or more holes in the resistance heater.

In accordance with some embodiments, the frame includes a transport arm lock region adapted to be attached to the transport arm of the dose withdrawal tool.

In accordance with an aspect of some embodiments of the present disclosure, an activating unit is provided for a dosage unit in accordance with any of the embodiments presented herein, which includes:

a dose pulling device adapted to move the dosage unit from a storage position to a use position;

a holder adapted to hold the dosage unit so that the biologically active agent is in hermetic alignment with the air channel of the activating unit; as well as

electrodes positioned to be in electrical contact with at least two electrical contact receiving areas of the resistive heating element of the dosage unit when in the activation unit.

In accordance with some embodiments, the dose withdrawal tool includes a dose withdrawal lever adapted to engage with the receiving area of the dose unit such that movement of the dose withdrawal lever moves the dose unit into or out of a position of use.

In some embodiments, the sealed alignment defines a path through the plate within the lumen along which air passing through the plate continues until it reaches the outlet.

In accordance with some embodiments, the holder includes a mechanism configured to move the dispensing unit.

In accordance with an aspect of some embodiments of the present disclosure, an inhalation device is provided that includes an activator unit according to any of the embodiments presented herein.

In accordance with some embodiments, an inhalation device includes a dosage unit nebulization apparatus that includes a plurality of dosage units in a closed container.

In accordance with some embodiments, the closed container includes an interlock that, upon spraying the first dosage unit from the container, prevents the second dosage unit from spraying out of the container until the first dosage unit is returned to the nebulizer.

In accordance with some embodiments, the dosing unit is sprayed into an evaporator, and the operation of the interlock includes placing the evaporator in the nebulizer of the dosing unit.

In accordance with some embodiments, the apparatus includes a clamping chamber apparatus that includes:

a compartment sized to receive the dosing unit from the dosing unit container while the clamping chamber apparatus is inserted into the dosing unit container, and

a power supply unit configured to, while the clamping chamber apparatus is removed from the dosing unit container, deliver a current to the resistive heating element of the suitably obtained dosing unit to vaporize the biologically active agent contained in the dosing unit.

In accordance with some embodiments, the dosage unit container contains a plurality of dosage units.

In accordance with some embodiments, the device is configured to release at least one predetermined vaporous amount of the biologically active agent upon controlled heating of the plate including the biologically active agent.

In accordance with some embodiments, the apparatus includes a temperature sensor for measuring temperature in one or more of the dosage units and on the dosage unit.

In accordance with an aspect of some embodiments of the present disclosure, there is provided a method of making a dosage unit in accordance with any of the embodiments presented herein, which includes:

contacting the carrier material with the isolated biologically active agent;

the formation of a plate that includes a carrier material containing a biologically active agent introduced therein and / or applied thereto; as well as

covering the plate on at least part of one side with an electrically resistive heating element.

In accordance with some embodiments, forming the plate includes:

placing a plurality of particles of a carrier material containing a biologically active agent incorporated therein and / or applied thereto into a dispensing chamber on a flat surface;

vibrating a flat surface until many particles are aligned; as well as

pressing the aligned plurality of particles to form a plate.

In accordance with some embodiments, forming the plate includes cutting a portion of the carrier material to form a single breathable matrix.

In accordance with some embodiments, cutting off a portion of the carrier material is performed prior to contacting the carrier material with the released biologically active agent.

In accordance with an aspect of some embodiments of the present disclosure, there is provided a method for pulmonary delivery of at least one biologically active agent to a patient, which comprises:

loading a dosage unit into an activating unit of an inhalation device in accordance with any of the embodiments presented herein;

applying a current to the resistive heating element of the dosage unit so as to vaporize a predetermined vaporous amount of the biologically active agent, thereby releasing a predetermined vaporous amount in a controlled manner.

In accordance with some embodiments, the method comprises, after applying a current, inhaling ambient air through the plate, thereby producing pulmonary delivery of a predetermined vaporous amount to the lungs of the patient.

In some embodiments, the predetermined vaporous amount is selected to exhibit at least one preselected pharmacokinetic profile and / or at least one preselected pharmacodynamic profile of the biologically active agent in the patient.

In accordance with some embodiments, the method further comprises:

determining at least one pharmacokinetic parameter and / or at least one pharmacokinetic variable and / or at least one pharmacodynamic parameter induced by pulmonary delivery of the isolated biologically active agent to the patient from the device; based on the pharmacokinetic parameter and / or the pharmacokinetic variable and / or the pharmacodynamic parameter, the determination of a predetermined vaporous amount that exhibits a preselected pharmacokinetic profile and / or a preselected pharmacodynamic profile of a biologically active agent in a patient; as well as

adjusting the device to deliver at least one predetermined vaporous amount of the biologically active agent.

In accordance with some embodiments, each of the pharmacokinetic parameter and / or pharmacokinetic variable and / or pharmacodynamic parameter is determined for an individual patient such that a predetermined vaporous amount is determined personally for the patient.

In accordance with some embodiments, the preselected pharmacodynamic profile ranges from a minimum level of a desired effect to a level of an undesirable effect.

In some embodiments, the pharmacodynamic profile ranges from a minimum level of a desired effect to a minimum level of an undesirable effect.

In accordance with some embodiments, the pharmacodynamic profile ranges from the minimum level of the desired effect to a level higher than the minimum level of the undesirable effect.

In accordance with some embodiments, determining at least one of a desired effect and / or an undesirable effect includes receiving instructions from a patient and / or a physician.

In accordance with some embodiments, the preselected pharmacodynamic profile is selected from the group consisting of:

pharmacodynamic profile within a level below the minimum level of therapeutic effect;

a pharmacodynamic profile ranging from the minimum level of therapeutic effect to the maximum level of therapeutic effect, where the adverse effect is not manifested or felt, and

pharmacodynamic profile within a level above the minimum adverse effect level.

In some embodiments, the pharmacodynamic profile ranges from a minimum level of therapeutic effect to a maximum level of therapeutic effect where no adverse effect is manifested or felt.

In accordance with an aspect of some embodiments of the present disclosure, there is provided a method of treating a condition being treated by inhalation of at least one predetermined vaporous amount of at least one biologically active agent using a method according to any of the embodiments presented herein.

In some embodiments, the condition is selected from the group consisting of alcohol abuse, amyotrophic lateral sclerosis, anorexia nervosa, anxiety disorders, appetite fluctuations, asthma, atherosclerosis, bipolar disorder, bladder dysfunction, chronic obstructive pulmonary disease (COPD) , collagen-induced arthritis, colorectal malignant tumor, Crohn's disease, delirium, diseases of the digestive system, Dravet syndrome, drug addiction and dependence, dystonia, epilepsy, fibromyalgia, generalized epilepsy with febrile seizures plus (GEFS +), glaucoma, glioma, hepatitis HIV-associated sensory neuropathic depression, Huntington's disease, high blood pressure, increased intraocular pressure, inflammatory bowel disease (IBD), insomnia, irritable bowel syndrome (IBS), lack of appetite, leukemia, migraine, movement disorders, ras multiple sclerosis (MS), nausea, neurogenic pain, neuropathic pain, nociceptive pain, Parkinson's disease, phantom pain, post-traumatic stress disorder (PTSD), premenstrual syndrome, pruritus, psychiatric disorders, psychogenic pain (psychogenic or somatoform pain), seizures, septic and cardiogenic shock, sexual dysfunction, skin tumors, sleep apnea, spasticity, spinal cord injury, tics, Tourette symptoms, tremors, unintentional weight loss and vomiting.

In accordance with an aspect of some embodiments of the present disclosure, a dosage unit is provided for pulmonary delivery of at least one biologically active agent to a user, which includes:

the frame containing the hole, and

a plate composed of a solid carrier material and suitably pressed into the hole;

the plate being sufficiently air permeable to provide a flow of at least 0.5 liters of gas per minute, at a vacuum of at least 1-5 kPa, through the plate.

In accordance with some embodiments, the dosing unit includes a resistive heating element in thermal contact with at least two opposing plate surfaces and extending over them, the plate together with the resistive heating element being sufficiently air permeable to provide a flow of at least 0. 5 liters of gas per minute at a vacuum of at least 1-5 kPa through a plate between at least two opposite surfaces.

In some embodiments, the plate is sufficiently air permeable to provide a flow of at least 0.5 liters of gas per minute at a vacuum of at least 1-5 kPa through the plate between at least two opposing surfaces.

In accordance with some embodiments, the carrier material has an electrical resistivity of at least 10 μΩ · m.

In some embodiments, the carrier material has a thermal conductivity of at least 0.1 W / (m⋅K).

In some embodiments, the carrier material is selected from the group consisting of glass, quartz, ceramic composite, silicon carbide, mullite, alumina, silicone, and polytetrafluoroethylene.

In some embodiments, the plate is a single breathable matrix.

In some embodiments, the plate is an air-permeable plurality of packaged particles.

In some embodiments, the particles have a diameter greater than 10 microns.

Unless otherwise indicated, all technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs. While methods and materials similar or equivalent to those described herein may be used in the practice or testing of embodiments of the present invention, some methods and / or materials are described below. In the event of a conflict, the patent description, including definitions, will be monitored. In addition, the materials, methods and examples are illustrative only and are not intended to be limiting.

As will be appreciated by those skilled in the art, aspects of the invention may be implemented as a system, method, or computer program product. Accordingly, aspects of the invention may take the form of an all-hardware embodiment, an all-software embodiment (including firmware, resident software, micro-code, and the like), or an embodiment combining software and hardware aspects, which may all generally referred to in this document as "electronic unit", "module" or "system". In addition, some aspects may take the form of a computer program product embodied in one or more computer-readable media having a computer-readable program code implemented thereon. The implementation of the method and / or system of embodiments may include performing or completing selected tasks manually, automatically, or a combination thereof. In addition, in accordance with the actual instrumentation and equipment of the method and / or system embodiments of the present disclosure, several selected tasks may be implemented in hardware, software, or firmware, or a combination thereof, using an operating system.

For example, hardware for performing selected tasks in accordance with some embodiments may be implemented as a chip or circuit. In software, the selected tasks, in accordance with some embodiments, may be implemented as a plurality of software instructions executed by a computer using any suitable operating system. In some embodiments, one or more tasks in accordance with some embodiments of a method and / or system as described herein are performed by a data processor, such as a computing platform, to execute a plurality of instructions. Optionally, the data processor includes nonvolatile memory for storing instructions and / or data and / or nonvolatile memory, such as a magnetic hard disk, and / or removable media for storing instructions and / or data. Optionally, a network connection is also provided. Optionally, a display and / or user input device such as a keyboard or mouse is also provided.

Brief Description of Drawings

Some embodiments of the present invention are described herein by way of example only with reference to the accompanying drawings. With a specific example of detailed graphics, it should be emphasized that the data is shown by way of example and for the purpose of illustrative discussion of embodiments. In this regard, the description, together with the drawings, makes it obvious to those skilled in the art how embodiments of the present invention may be implemented.

Graphic materials are:

FIG. 1A-M are schematic views of a disassembled and assembled dosage unit (cartridge) and some of its alternative designs, in accordance with some embodiments.

FIG. 2A-E schematically illustrate a carousel-type dose delivery system for use in or as an inhalation device, in accordance with some embodiments.

FIG. 3A-B schematically illustrate a clamping chamber apparatus for vaporizing and delivering a biologically active agent from a dosage unit, in accordance with some embodiments.

FIG. 4A-B schematically illustrate a device for loading from a carousel and independent of the carousel for vaporizing and delivering an isolated biologically active agent from a dosage unit, in accordance with some embodiments.

FIG. 5 is a schematic illustration of a dose blocker protected nebulization apparatus, together with a removable dose delivery assembly, in accordance with some embodiments.

FIG. 6 is a schematic diagram of a system including an inhalation device, a physician interface, and / or a patient interface, in accordance with some embodiments of the present invention.

FIG. 7 illustrates a flow diagram of a method for administering a personalized treatment regimen to a patient in accordance with some embodiments of the present invention.

FIG. 8A-D are schematic diagrams (FIG. 8A) and screen views (FIGS. 8B-D) of a clinician's interface for selecting and prescribing a treatment regimen to a patient in accordance with some embodiments of the present disclosure.

FIG. 9 is a flow diagram of a method for obtaining a personal pharmacodynamic parameter (PD) from a patient and modifying a treatment regimen, respectively, in accordance with some embodiments of the present invention.

FIG. 10A-E are images from patient interface screens (FIGS.10A, 10C, 10E), as well as graphical representations of the expected pharmacodynamic and pharmacokinetic profiles of the patient before and after obtaining a personal PD effect (FIGS.10B and 10D, respectively), in accordance with some embodiments of the present invention.

FIG. 11 is a flow diagram of a method for producing one or more biomarkers using a personal portable device and / or using an inhalation device, and if necessary, modify the dose and / or treatment regimen accordingly, in accordance with some embodiments of the present invention.

FIG. 12A-C are screen images of a patient interface containing various applications for obtaining biomarkers and / or for assisting a patient in determining a perceived therapeutic and / or adverse effect, in accordance with some embodiments of the present invention.

FIG. 13 is a schematic diagram of an inhalation device configured to provide automated controlled pulmonary delivery of one or more active agents, in accordance with some embodiments of the present invention.

FIG. 14A-B are a schematic diagram of a configuration of an inhalation device (FIG. 14A) and a dosage unit of an inhalation device comprising discrete plates (FIG. 14B), in accordance with some embodiments; as well as

FIG. 15 is a flow diagram of a method for treating an individual patient using the system of FIG. 9 while maintaining the patient in a personalized therapy window, in accordance with some embodiments of the present invention.

Detailed description of the invention

The present invention, in some of its embodiments, relates to the field of pharmacology, and more specifically, but not exclusively, to methods and devices for controlled delivery by inhalation of volatiles.

Before explaining at least one of the embodiments of the present invention in detail, it should be understood that the present disclosure is not necessarily limited in its application to the details of the construction and arrangement of components and / or methods set forth in the following description and / or illustrated in the drawings and / or example examples.

The difficulties associated with the controlled delivery by injection and / or ingestion of biologically active (pharmaceutically active) agents that are characterized by low water solubility and / or high viscosity and / or high boiling points lead the present inventors to consider the delivery of such biologically active agents. through evaporation and inhalation. As noted above, methods and devices for pulmonary delivery (inhalation) of volatile biologically active agents from herbal substances containing them have been shown to be very effective and contribute to widely accepted pharmaceutical standards and practices. However, these methods and devices have not been developed to deliver isolated biologically active agents, namely agents that no longer form part of the plant matter.

While seeking a comprehensive solution to the problem of the controlled and reproducible delivery of a predetermined amount of an isolated volatile biologically active agent by inhalation, the inventors have contemplated a dosage unit that includes a plate containing at least one isolated biologically active agent in a carrier material and / or on it, and a heating element in thermal contact and passing over the plate, so that the biologically active agent evaporates from the plate when current is applied to the heating element. A dosage unit includes an amount of a biologically active agent that corresponds to one or more cycles (doses) of application, and can be used in an inhalation device that controls the intensity and duration of heating and / or air flow through the dosage unit during inhalation, thereby delivering a controlled and reproducible predetermined vaporous amount of the biologically active agent to the subject.

Method for vaporizing and inhaling an isolated biologically active agent: In accordance with an aspect of some embodiments, there is provided a method for pulmonary inhalation of at least one biologically active agent to a patient using an inhalation device that is configured to controlled release by vaporizing one or more biologically active agents from dosage unit containing the isolated biologically active agent (s).

This method is a mode of administration by inhalation of a vaporous biologically active agent that would otherwise be difficult to administer by swallowing and / or injection for practical reasons, the requirement of the patient, as well as the intrinsic properties of some isolated biologically active agents, which makes them unsuitable or otherwise undesirable for administration by swallowing and / or injection. Optionally, the method for pulmonary inhalation of at least one biologically active agent to a patient includes a metered dose inhalation device (MDI device), which is an inhalation device configured for controlled release by evaporation of at least one predetermined vaporous amount of one or more biologically active agents. active funds.

In some embodiments, the term "inhalation" refers to the act of a user / patient voluntarily and deliberately inhaling ambient air through a device so as to introduce a vaporous agent into the lungs. It should be noted that, in some embodiments, spontaneous breathing may also carry vaporous means to the lungs, as well as involuntary respiration produced by a mechanical ventilation / breathing device, as such devices are known in the art.

In some embodiments, the dosage unit is designed to contain a predetermined and predetermined amount of biologically active agent or an isolated biologically active agent. In some embodiments, the amount corresponds to a single dose taken from time to time or as part of a treatment regimen. In some embodiments, the dosage unit is designed to include an amount of an isolated biologically active agent that corresponds to more than one dose taken from time to time or as part of a treatment regimen. Therefore, the dosage unit may include several unit doses contained separately in the dosage unit or contained in combination and evaporated in predetermined aliquots. The amount of biologically active agent released in one dose can be calculated taking into account the efficiency of evaporation of the biologically active agent.

As used herein, the term "evaporation" in all its inclinations refers to a non-combustible process in which a substance is transported in the form of gas (vapors), mist, droplets suspended in the inhaled atmosphere, or aerosol. In some embodiments, "vaporization" means that the substance is rendered transportable in the form of gas (vapors) when heated. In some embodiments, during inhalation delivery, vapors may cool and condense to form a mist, such as droplets or aerosols in suspension in the inhaled atmosphere. In the context of some embodiments, the term "evaporation" encompasses a liquid-to-gas phase transition (evaporation and boiling) as well as a solid-to-gaseous phase transition (sublimation). In some embodiments, the term "evaporation" also includes the intermediate state of partially condensed vapors that form small droplets that are suspended in the inhaled atmosphere to form a mist or aerosol. In some embodiments, the term "evaporation" refers to a process in which the isolated substance is transportable as a gas or droplets suspended in a respirable atmosphere, namely that the substance of choice is essentially the only substance that evaporates, devoid of a carrier, or any other notable component other than the inhaled atmosphere. In some embodiments, the term "evaporation" excludes pulverization (the transformation of liquids into fine sprays of fine droplets containing many substances in a liquid state, or the transformation of liquids into an aerosol or mist, also called fine spray), as well as other modes of transport of substances in the form fine solid particles containing many substances (powder).

In some embodiments, the term "evaporation" excludes processes in which a substance is dissolved, suspended, emulsified, or otherwise mixed with a liquid carrier, and then brought into a transportable form in the form of a mist that includes a liquid carrier or an aerosol that includes a liquid carrier.

In some embodiments, evaporation is performed by heating the substance to a temperature sufficient to raise the partial pressure of the vaporized substance without causing combustion of the substance (below the combustion temperature). Typically, evaporation is carried out by heating the substance to a temperature just below, equal to or above its normal boiling point at atmospheric pressure. In some embodiments, evaporation is performed by increasing the temperature of the substance and lowering the ambient pressure (using negative pressure or vacuum). Depressurization of the environment is usually carried out by inhalation, which produces a negative pressure in the atmosphere surrounding the substance, usually in the range of 5-50 mbar lower relative to atmospheric pressure (negative pressures or from -5 to -50 mbar ).

As used herein, the term "vaporous amount" refers to the amount of agent that is in the form of vapor, the amount of vaporous form being obtained by heating elements in the apparatus, if necessary taking into account the removal of vapor by air flow. It should be noted that in this document, according to some embodiments, the amount of vaporous agent in the context of the present disclosure is not an estimated amount, but an actual amount evaporated by said heating, as measured directly by standard laboratory methods.

The term "predetermined vaporous amount" refers to the amount that is intentionally released by the MDI device from the dosage unit, the amount of which is determined by the design of the dosage unit, device settings, and / or treatment protocol as described herein.

The terms "bioactive agent", "pharmaceutically active agent", "biologically active agent" and "agent" are used interchangeably herein and refer to a compound, polymer, drug, conjugate or complex, or any combination thereof, which has a somatic and / or a psychotropic effect when administered to a subject. Typically, the biologically active agent has the desired and / or beneficial and / or therapeutic effect when it is delivered pulmonary, and then through the systemic pathway (for example, blood, lymph) to the target organ (s) and / or target system (and ). The agent can be of natural or synthetic origin. Non-limiting examples of active agents include central nervous system active agents, chemotherapeutic agents, sedatives, analgesics, and psychotropic agents.

As used herein, the term "isolated biologically active agent" refers to a biologically active agent that is produced synthetically, or a biologically active agent that is extracted from a natural product.

In some embodiments, the term "isolated biologically active agent" refers to a substantially purified material, as opposed to, for example, a natural product such as a plant material, which also contains solid insoluble components such as cellulosic materials.

The term "isolated biologically active agent" is intended to encompass the entire extraction or selective extraction of one or more substances recovered from a natural product as a soluble fraction.

In some embodiments, the term "isolated biologically active agent" refers to a soluble fraction of an extracted preparation that is substantially miscible with one or more solvents and / or mixtures of solvents and / or can substantially dissolve therein. The term "substantially dissolves" means that at least 90% by weight of the total weight of the isolated biologically active agent is dissolved in one or more solvents without degradation of the biologically active agent, while less than 10%, less than 8% , less than 5%, less than 3% or less than 1% of the insoluble solid mass remains undissolved in the fraction. "Substantially miscible" means that at least 90% by weight of the total weight of the isolated biologically active agent is in any form (eg, liquid, gum, or soluble powder) that can be combined with one or more solvents without biodegradation. active agent for the formation of a clear liquid, while less than 10%, less than 8%, less than 5%, less than 3% or less than 1% of the insoluble solid mass remains undissolved in the fraction. In the context of some embodiments, the isolated biologically active agent is substantially devoid of or contains less than 10%, less than 8%, less than 5%, less than 3%, or less than 1% by weight of insoluble matter, insoluble fraction, or insoluble component. The term "insoluble" refers to a substance that does not dissolve in a solvent or solvent mixture where the isolated biologically active agent dissolves.

In some embodiments, the amount of isolated biologically active agent that is soluble in one or more solvents is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% by weight of the total weight of the isolated biologically active agent.

In some embodiments, an "isolated biologically active agent" refers to a biologically active agent that can be substantially evaporated without leaving a significant residue, or includes it. By the term "substantially evaporated without leaving a significant residue" is meant that at least 50% by weight of the total weight of the biologically active agent evaporates without degradation, while less than 50% by weight remains unevaporated. In some embodiments, the amount of biologically active agent that is capable of volatilizing substantially without degradation and leaving no significant residue is at least 50%, 60%, 70%, 80%, 90%, 95%, or 99% by weight of the total the mass of the biologically active agent.

In the context of some embodiments, the isolated biologically active agent is substantially free of non-volatile material, non-volatile fraction, or non-volatile component. The term "nonvolatile" refers to a substance or mixture of compounds that does not substantially evaporate under the conditions (e.g., temperature) used to evaporate at least 50% of the recovered biologically active agent and / or that degrade or burn before boiling or otherwise to form their vapors, and / or have a boiling point higher than the temperature used to vaporize at least 50% of the recovered biologically active agent.

In some embodiments, the isolated biologically active agent is a product of the extraction process that has been separated from other substances without further purification. In some embodiments, the content of the isolated biologically active agent in the crude extract is at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70% by weight at least 80%, at least 90%, at least 95% or at least 98%, based on the weight of the crude extract containing the isolated biologically active agent.

In some embodiments, the isolated biologically active agent is a product of an extraction process or a product of a synthetic process that has been isolated from other materials and purified. In some embodiments, the purity of the isolated biologically active agent is at least 90%, at least 95%, or at least 98% purity by weight based on the weight of the sample containing the isolated biologically active agent.

In some embodiments, the term "isolated biologically active agent" refers to a combination of biologically active agents, each of which can have different or similar effects and / or have a synergistic effect when combined (the cumulative effect of each alone is less than the effect of the combination).

In some embodiments, "total extraction" refers to a process in which a naturally occurring product is treated to allow a soluble fraction of its components to dissolve in a specific solvent, while water can extract the aqueous fraction and an organic solvent or inert gas can afford the organic fraction.

"Selective extraction" is a process in which a complete fraction or total extraction is further processed in various stages and with various solvents to obtain a paste, resin or powder containing essentially one or more substances selected for their solubility in selected solvents. thus obtaining a selective extraction, which consists mainly of several selected main components (two, three, four, five, six, seven, eight, nine or ten substances or compounds), referred to herein as a "co-extract".

The complete extract and / or combined extract and / or a single extracted and purified substance can each be converted into an isolated biologically active agent by substantially removing (e.g., evaporating) the solvent (s), thus obtaining an isolated biologically active agent, possibly in the form of a liquid resin or dried powder containing the corresponding solvent-soluble substances.

For example, while a sample of a plant of natural origin, cultivated or bred, may contain one or more biologically active agents, as well as a variety of other substances and insoluble substances of plant origin, the sample of an isolated biologically active agent may consist mainly of one substance or compound. , and a co-extracted sample of isolated biologically active agents may consist mainly of several (two, three, four, five, six, seven, eight, nine or ten) substances or compounds that represent the main components of the sample, while minor components and impurities are less than 40%, less than 30%, less than 20%, less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2% or less than 1% of the sample in units of mass.

In embodiments in which the biologically active agent is prepared synthetically, the reaction product may contain the biologically active agent mixed with a variety of different reagents, side reaction products, solvent (s) and other substances, and thus the sample of the isolated biologically active agent is further processed and purified to substantially consist of one desired substance or compound, while impurities are less than 10%, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less 3%, less than 2% or less than 1% of the sample in units of mass.

In the context of some embodiments, the isolated biologically active agent is substantially free of solvent, insoluble substance or carrier, namely, it is not in solution, emulsion or suspension and is not mixed with other substances, unless combined with other isolated biologically active agents, all of which are intended for co-delivery, regardless of whether some of them are dissolved or suspended, or found in emulsion with any other isolated biologically active agents.

In embodiments that combine more than one isolated biologically active agent, the combination is encompassed by the term “isolated biologically active agent” as defined herein, each of the biologically active agents being intended for pulmonary co-delivery to a patient. As used herein, the term "co-delivery" means that two or more biologically active agents are delivered to a patient in the same inhalation step and / or are present in and / or on a single dosage unit.

Used in this document, the term "pure" refers to the amount of one identified and specific substance, in relation to the total amount of a mixture of a substance with other substances, which is more than 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, more than 99%, more than 99.5%, more than 99.9% or 100% of the total mass of the mixture.

Isolated biologically active agents, in accordance with some of the embodiments presented herein, include, without limitation:

synthetically obtained and purified (95% purity) biologically active agent;

a combination of two or more separately synthesized and purified (95% purity, each) biologically active agents;

a biologically active substance or a combination of more than one biologically active substance of natural origin, which is extracted from a microorganism, plant or animal and is further purified to approximately 90% purity (purified extract);

whole / complete extract of a microorganism, plant or animal, which is fractionated in an aqueous solution or an organic solvent (depending on what the biologically active agent or combination of biologically active agents is more soluble in), dried and used without further purification;

selective extract of a microorganism, plant or animal, which is fractionated sequentially in various aqueous and organic solutions to achieve additional isolation of one or more biologically active agents from some components of the extract, dried and used without additional purification;

a combination of more than one purified, whole or selective extract, each of which contains one or more biologically active agents;

a combination of one or more synthetically obtained and purified biologically active agents with one or more purified, whole or selective extracts, each of which contains one or more biologically active agents.

The method described herein solves the problem of the controlled and reproducible administration of certain types of biologically active agents using some of the most prevalent and acceptable modes of administration, such as oral and intravenous / subcutaneous injection. For example, hydrophobic biologically active agents that are substantially immiscible in aqueous media and / or physiological fluids may have low absorption, low distribution, and low bioavailability upon ingestion or injection. As is known in the art, the likelihood that a compound may be useful as a medicine increases if the compound exhibits some degree of solubility in aqueous media; Lipinski's rule of five refers to the octanol-water partition coefficient (log P) and indicates that the compound should have a log P less than 5, with compounds exhibiting a log P greater than 5 considered too hydrophobic for most drug administration regimens , which leads to poor absorption and distribution in the body. It should be noted herein that embodiments of the present disclosure are not limited to hydrophobic biologically active agents, and therefore isolated biologically active agents having a log P of less than 5 are also contemplated. For example, in some embodiments, the isolated biologically active agent (s) have a log P greater than 1.

The devices and methods provided herein are useful for administering any isolated biologically active agent that can evaporate regardless of its hydrophobicity, including agents exhibiting high log P values. In some embodiments, the isolated biologically active agent has a value log P in the temperature range 20-37 ° C, which is more than 3, more than 4, more than 5, more than 6, more than 7 or more than 8.

The devices and methods provided herein are useful for administering hydrophobic isolated biologically active agents as a vaporized agent and delivered by inhalation as a gas (vapor of the agent).

Another factor that limits the use of some isolated biologically active agents is their physical form, namely, whether they are a rare or viscous liquid or solid in their isolated form.

The devices and methods provided herein are contemplated to be useful for administering any isolated biologically active agent that is volatile regardless of its physical form, including agents that are viscous liquids. In some embodiments, the isolated biologically active agent has a viscosity of at least 10 centipoise (cps), at least 20 cps, at least 30 cps, at least 40 cps, at least 50 cps, at least 60 cps at least 70 cps, at least 80 cps, at least 90 cps, at least 100 cps, at least 200 cps, at least 300 cps, at least 400 cps, at least 500 cps, at least at least 1000 cps, at least 2000 cps, at least 5000 cps, or more than 10,000 cps.

The methods and devices provided herein are suitable for vaporizing a wide variety of isolated biologically active agents, including those with relatively high boiling points. In some embodiments, the isolated biologically active agent has a boiling point above 80 ° C, above 100 ° C, above 150 ° C, above 200 ° C, above 250 ° C, above 300 ° C, above 350 ° C, above 400 ° C. , above 450 ° C, above 500 ° C, above 550 ° C, above 600 ° C, above 650 ° C, above 700 ° C or above 750 ° C.

The methods and devices provided herein are suitable for vaporizing a wide variety of volatile recovered biologically active agents, regardless of their physical form, hydrophobicity, viscosity and / or boiling point, as long as they are volatile. As used in the context of some embodiments, the term "volatile" refers to the property of a substance that determines its suitability for pulmonary delivery by evaporation and inhalation.

This property corresponds to the boiling point or sublimation point of the substance, which can be in the range from 80 ° C or even 100 ° C to 750 ° C.

In some embodiments, the isolated biologically active agent that is effectively delivered to the patient in a predetermined and reproducible therapeutic amount is a sticky, thick, viscous and oily (hydrophobic with a log P greater than 5) liquid having a relatively high boiling point in the vapor phase without co-administration, whether intentionally or unintentionally, of any excipient, carrier, or any other inactive or undesirable substance with it.

As is known in the art, members of the cannabis family contain various volatile biologically active agents that have been found to have beneficial therapeutic effects in humans. In some embodiments, the biologically active agent is or includes a cannabinoid derived and purified from cannabis, or a synthetically produced and purified cannabinoid. In some embodiments, the isolated biologically active agent is an isolated cannabinoid such as, for example, Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerols (CBG), cannabichromenes (CBC), cannabinol (CBN), cannabinodiol (CBDL), cannabicyclol (CBL), cannabielsoin (CBE), cannabidivarin (CBDV), tetrahydrocannabivarin (THCV), cannabitriol (CBT), and any isomer and / or combination thereof.

It should be noted that other volatile isolated biologically active agents are included within the scope of this disclosure, including, without limitation, natural biologically active agents from extracts or synthetic origin, such as salvinorin, cationin, pucatein, thujone, damianin, bulbocapnin, cavalactones, lagochilin, lactucaria, glaucine, ergine, ibogaine, aporphine and leonurin, and synthetic volatilized isolated biologically active agents such as atropine, buprenorphine, butorphanol, fentanyl, hydromorphone, methadone, midazolam, nalbuphine, naloxone, naltrexon, oxypentaniline, rhypentanilicodone, rhypotinicodone sildenafil, sufentanil, and zolpidem.

In some embodiments, the isolated biologically active agent includes joint extracts or synthetic combinations of biologically active agents containing terpenes, flavonoids, nitrogenous compounds, and other natural and synthetic compounds. For example, certain combinations of cannabinoids, terpenes and flavonoids have been shown to modulate the effect of cannabinoids or even have a synergistic effect when compared to the effects of cannabinoids themselves.

Terpenes and terpenoids include, but are not limited to, Δ3-carene, β-selenene, β-pinene, β-pellandrene, β-farnesene, β-caryophyllene, β-pinene, β-eudesmol, α-terpinolene, α-pinene, α -fellandrene, α-humulene, α-bergamotene, α-terpineol, α-terpinene, α-pinene, α-humulene, α-guayen (t), α-cedrene, α-bisabolol, valensen (t), trans-ocymene , trans-ocymene, trans-caryophyllene, terpinolene, trans-2-pinanol (t), selina-3,7- (11) -diene, selina- (11) 3,7-diene (t), sabinene girdat, nerol , myrcene, myrcene, menthol, linalool, limonene, limonene, isoborneol, guayol, guaya-11, (10), 1-diene (t), germacrene B (t), geraniol, farnesene (t), eudesm-7 (11 ) -en-4-ol (t), elemene (t), cis-ocymene, cis-ocymene, caryophyllene oxide, caryophyllene oxide, camphor, camphene, borneol and (+) fenchol.

Flavinoids include, but are not limited to, cannflavin A, cannflavin B, cannflavin C, vitexin, isovitexin, apigenin, kaempferol, quercetin, luteolin, and orientin.

In some embodiments, the biologically active agent is an isolated isomer of any of the aforementioned cannabinoids, such as, for example, (-) - trans-Δ ⁹ -tetrahydrocannabinol, also known as dronabinol, which is a THC isomer. The isolated dronabinol, like the other THC isomers, exhibits a water solubility of 0.0028 mg / ml at 23 ° C, a log P value of 5.648, a boiling point of 157 ° C and a viscosity of 85-140 cps.

Dosing unit:

Due to the chemical and physical properties of some volatile, isolated biologically active agents, the route of administration by inhalation of such biologically active agents is carried out by using an individual dosage unit, also referred to herein interchangeably as a cartridge, which is designed and configured to allow evaporation and inhalation of at least at least one biologically active agent to a user (eg, a patient). As discussed above, the biologically active agent may be, in some embodiments, an isolated biologically active agent having one or more properties that render administration less effective or even ineffective when swallowed and / or injected into a user.

In accordance with an aspect of some embodiments, a dosage unit is provided for pulmonary delivery of at least one biologically active agent to a user, it includes a plate and an electroresistive heating element, also referred to herein interchangeably as a resistance heating element (e.g., a metal resistance heating element) , in thermal contact with at least a portion of the surface of the plate and extending thereon, the plate comprising a solid carrier material and a predetermined amount of a biologically active agent in and / or on the carrier material.

In some embodiments, the resistive heating element extends over at least two opposite surfaces of the plate.

FIG. 1A-B are schematic illustrations of a dosage unit (vaporization cartridge or cartridge), in accordance with some embodiments, showing a dosage unit 2300 comprising a plate 2304 housed in an opening 2303 in a frame 2308 that forms part of a housing 2301 (FIG. 1A), and a resistive heating element 2306 in thermal contact with at least two opposing plate surfaces and extending thereon 2304 (FIG. 1B). FIG. 1C-M provide schematic illustrations of alternative dosage unit designs, in accordance with some embodiments.

As used herein, the term "plate" refers to a mixture of chemically bonded substances that make up a matrix or platform for processing, maintaining, storing, dispensing and delivering a substance that is otherwise too dispersible to handle, contain, distribute and / or deliver itself. by itself (for example, liquid, paste, fine powder, particles, or sticky resin). The plate, for example, allows the distribution of a thick liquid and further allows vaporization and subsequent delivery from the plate.

Optionally, the liquid, paste, or sticky resin is dried and / or otherwise solidified after being incorporated into the plate. In some embodiments, the plate includes any substance that remains and is not delivered to the patient when heat is applied to it.

In accordance with embodiments, the plate comprises a solid carrier material that is selected and designed to allow the released biologically active agent to be vaporized and inhaled therefrom. Since the carrier material is used to carry and dispense a volatile biologically active agent, it is determined by several chemical and physical criteria, which include one or more of the following:

essentially does not react (chemically inert) with the biologically active agent when in contact with it, at least in the temperature range from as low as the lowest expected storage temperature to as high as the operating temperature, possibly with some a wider range of confidence intervals (for example, from 50 ° C below the storage temperature to about 50 ° C above the operating temperature). In some embodiments, the storage temperature may be lower than about -80 ° C or about -40 ° C or -20 ° C, however, higher and lower temperatures are within the scope of the present invention, including, for example, room temperature. temperature (for example, 18-26 ° C). The carrier material is chemically inert at temperatures up to (at least) the maximum vaporization temperature of the biologically active agent (or slightly higher, for example, by 50 ° C) or up to the combustion and / or decomposition temperature of the biologically active agent, however, higher temperatures are within the scope of the present invention;

characterized by a combustion and / or decomposition and / or melting temperature higher than the combustion / decomposition of the biologically active agent, however, carrier materials with higher combustion and / or decomposition and / or melting temperatures are considered within the scope of the present invention;

characterized by a specific thermal conductivity of at least 0.1 W / (m⋅K) (which allows the carrier to easily distribute heat over the plate); as well as

characterized by a specific electrical resistance of at least 10 μΩ⋅hm (reducing the ability of the carrier to reduce the current passing through the resistive heating element).

In the form of a mixture of chemically bonded substances containing a carrier material and a biologically active agent (loaded plate), the loaded plate is essentially breathable. In other words, the loaded plate is characterized by a structure that allows the flow of inhaled gas (typically the surrounding atmosphere, whether or not the agent is carrying vapors) to pass through it. In some embodiments, the plate structure is characterized by the passage of inhaled gas therethrough, while the passage is defined by at least 2 liters of gas per minute (L / min), at least 1.5 L / min, at least 1 L / min. at least 0.8 l / min or at least 0.5 liters of gas per minute, at a vacuum of at least 1-5 kPa, which corresponds to the thrust force corresponding to the entry of air into the user's lungs, while the average pulmonary the peak in a healthy adult is approximately 25 mbar. According to some embodiments, the plate structure is characterized by allowing a minimum flow of 0.5 liters per minute and a maximum negative (thrust) pressure of 25-40 mbar or a negative pressure of 1-5 kPa (-1 to -5 kPa) near the plate ...

In order for the plate to be air-permeable, it can, for example, be made in the form of a single porous matrix or contain a plurality of closely or loosely packed individual porous and / or non-porous particles. In some embodiments, in which the plate is made up of a plurality of separate (non-fused) particles, it is generally surrounded by walls having holes on two opposite surfaces to allow gas flow through them, hence the article is larger than the holes.

In accordance with some embodiments, the plate structure has a surface / weight ratio of at least 1000 square meters per gram (m ² / g).

In accordance with some embodiments, the plate structure has a surface / weight ratio of at least 500 square meters per gram (m ² / g).

More specifically, as used in the context of some embodiments, the term "carrier material" is a solid wafer material that provides physical support for a volatile biologically active agent or thermally volatile material that is included in the wafer.

In accordance with some embodiments, the biologically active agent is not supplied to the electrically resistive heating element, but is applied to and / or on the carrier material. In some embodiments, the biologically active agent and the resistance heating element are not in direct physical contact, but are in thermal contact through at least the plate.

In accordance with some embodiments, the carrier material or plate containing it has at least one of the following properties:

chemical compatibility and compliance;

relatively high combustion / decay / melting temperature; physical unity, homogeneity and integrity; porosity;

high thermal conductivity; as well as low electrical conductivity.

In the context of some embodiments, the implementation of chemical compatibility and compliance can be considered as a requirement for substantial chemical stability and inertness, purity and absence of extractable and leachable substances, and mechanical integrity.

The carrier material must be chemically stable and inert (not reacting) with respect to the biologically active agent and components that make up the dosage unit of the inhaler (cartridge) provided herein, as well as other components of the inhalation device, at least in the full range between storage conditions and the operating conditions of the device and cartridge. In some embodiments, chemical inertness is also required during the process of making the plate and / or dosage unit, such as stability and chemical inertness in contact with polar and / or non-polar solvents that can be used in the process and / or over a range of temperatures or other conditions. used in the production process. Chemical stability and inertness can be determined by the percentage of the carrier material or its constituents that undergo a chemical or physical change during the process, storage and use of the cartridge provided herein, and / or the amount obtained from the carrier material (referred to in this document as "extractable and leachable") that are inhaled during use of the dosage unit provided herein, in accordance with the Pharmacopoeia and other widely used standards and practices known and available to any person skilled in the art. One skilled in the art will be able to accomplish the foregoing by following commonly practiced guidelines as provided, for example, in publications provided publicly by the Product Quality Research Institute (PQRI); in textbooks such as "Leachables and Extractables Handbook: Safety Evaluation, Qualification, and Best Practices Applied to Inhalation Drug Products", 2008, Editors: Douglas J. Ball, Daniel L. Norwood, Cheryl L.M. Stults and Lee M. Nagao, Publisher: John Wiley & Sons, Inc., and peer-reviewed scientific articles such as "Best practices for extractables and leachables in orally inhaled and nasal drug products: an overview of the PQRI recommendations" by Norwood, DL et al., Pharm Res., 2008, 25 (4), p. 727-39.

The carrier material is additionally selected so that it is resistant to heat at the temperature at which the biologically active agent evaporates or at a slightly higher temperature. In other words, the carrier material is selected to exhibit a combustion, decomposition and / or melting temperature higher than the temperature used in preparing the dosage unit and higher than the temperature at which the dosage unit is used to vaporize the biologically active agent during inhalation. For example, in embodiments using a biologically active agent having a boiling point of about 250 ° C, the carrier material is selected so that it is chemically and mechanically stable when heated to the temperature used to vaporize the biologically active agent, thus the material is the carrier is selected with a combustion temperature and / or decomposition temperature and / or melting point above 250 ° C, above 270 ° C, above 290 ° C, above 300 ° C, above 320 ° C, above 350 ° C, above 400 ° C, above 450 ° C, above 500 ° C, above 600 ° C, above 700 ° C or above 750 ° C. For example, quartz, glass, ceramic materials and some organic and inorganic polymers are characterized by a combustion temperature and / or decomposition temperature, and / or a melting point higher than the boiling point of the biologically active agent, about 250 ° C.

In some embodiments, the carrier material is made of one or more materials that include, but are not limited to, glass, quartz, ceramic composite, silicon carbide, mullite, alumina, carbon species (such as carbon, activated carbon, graphene, graphite, fullerenes and the like), silicone and polytetrafluoroethylene.

The requirement of physical cohesion, homogeneity and integrity corresponds to chemical conformity in the sense that the carrier material is selected in such a way that it maintains physical and mechanical integrity (not brittle or crumbly) to the extent that it can be transported and used to prepare the plate. for the intended dosage unit. In other words, the carrier material is selected so that it does not break or crumble to particles that are not uniform in size and shape, and in particular smaller than the intended particle size of the carrier material (see porosity requirement below). upon subsequent processing into a plate during preparation or during use of the inhaler dosage unit. Carrier materials can thus be selected according to the brittleness, ductility and tough-brittle transition temperature, as they are known and available to any person skilled in the art of materials science, while at the same time taking into account the stress that is applied to the material. the carrier during the preparation of the dosage unit presented herein; and the temperatures to which the carrier material in the dosage unit is exposed during its use, as described herein.

The air permeability, porosity of the carrier material, or the characteristics of the plate containing it are determined, in accordance with some embodiments, in terms of the flow of air that can be passed through the plate under inhalation pressure when the active agent is applied to and / or incorporated into the carrier material. Thus, the carrier material is selected suitable for the formation of the plates, which allows an air flow of at least 0.5 liters of gas per minute (0.5 / min) or even 1 liter / min under the action of a vacuum of at least 1-5 kPa , with a predetermined amount of biologically active agent applied to it or introduced into it. In some embodiments, the carrier material is in the form of a plurality of particles having a shape that allows gas to pass between them when packing the plate as described herein. In some embodiments, the particles of the carrier material are in the form of beads or spheroids. It should be noted that the spherical particles are easier to handle during the preparation of the dispensing unit provided herein.

Also contemplated are particles of carrier material in the form of fibers, film, or any other form that can be packaged in a breathable plate. In some embodiments, the carrier material particles are larger than the size of the holes in the breathable containment mesh or woven mesh containing an electroresistive heating element (e.g., a metal resistance heating element) forming part of a dosage unit, for example, are greater than 10 μm, 15 μm. 20 microns, 25 microns, 30 microns, 35 microns, 40 microns, 45 microns or more than 50 microns.

In some embodiments, the carrier material is in the form of a single monolithic breathable matrix defining the plate. The breathable matrix can be formed by fusing the carrier material particles in a process generally referred to as sintering and / or any other technique for forming solid foams and other breathable matrices within the skill of the art.

The carrier material from which the plate is made is selected so that it has thermal conductivity, which promotes efficient and uniform heating and evaporation of the biologically active agent applied to it or introduced into it. The thermal conductivity of the carrier material is therefore higher than that of paper and other dried plant material such as cannabis flowers and is approximately 0.01 W / (m⋅K). For example, the thermal conductivity of the carrier material is at least 0.1 W / (m⋅K), at least 0.2 W / (m⋅K), at least 0.3 W / (m⋅K), according to at least 0.4 W / (m⋅K), at least 0.5 W / (m⋅K), at least 0.6 W / (m⋅K), at least 0.7 W / ( m⋅K), at least 0.8 W / (m⋅K), at least 0.9 W / (m⋅K), at least 1 W / (m⋅K), at least 5 W / (m⋅K), at least 10 W / (m⋅K), at least 20 W / (m⋅K), at least 50 W / (m⋅K) or at least 100 W / ( m⋅K). For example, a carrier material containing silicone epoxy resin has a thermal conductivity of about 0.15-0.32 W / (m⋅K), a carrier material containing polytetrafluoroethylene (PTFE) has a thermal conductivity of about 0.25 W / (m⋅K) K), a carrier material containing glass has a thermal conductivity of approximately 1 W / (m⋅K), a carrier material containing quartz has a thermal conductivity of approximately 3 W / (m⋅K), and a carrier material containing Cr / Ni steel (18% Cr, 8% Ni), has a thermal conductivity of approximately 16.3 W / (m⋅K).

In some embodiments, the carrier material is different (not) from natural plant material, different from natural and chemically untreated plant material, and different from natural and mechanical untreated plant material. In some embodiments, the carrier material is devoid of natural, chemically untreated and / or natural, mechanically untreated plant material. For example, paper can be defined as both chemically and mechanically treated plant material, while pieces of plant material pressed into a plate are considered in the context of the present disclosure as chemically untreated plant material.

The carrier material from which the wafer is made is selected to have low electrical conductivity or high resistivity in order to avoid current passing through it, rather than through the built-in resistance heating element or resistance grid. For example, the carrier material is selected with a resistance greater than 1 μΩ⋅hm at 20 ° C, which roughly corresponds to the resistivity of the nichrome alloy used in the electrically resistive heating element. Therefore, the resistivity of the carrier material is at least 10 μΩ⋅hm, at least 50 μΩ⋅hm, at least 100 μΩhm, at least 200 μΩhm, at least 400 μΩ⋅hm, at least at least 600 μΩ⋅hm, at least 800 μΩ⋅hm, or at least 1000 μΩ⋅hm (1 mΩ⋅hm). For example, a carrier material containing polytetrafluoroethylene (PTFE) has a resistance of about 10 ²³ -10 ²⁵ Ohm⋅m, a carrier material containing glass has a resistivity of about 10 ¹¹ -10 ¹⁵ Ohm⋅m, and a carrier material containing fused silica, has a resistance of approximately 7.5x10 ¹⁷ Ohm⋅m.

In some embodiments, the carrier material can be formed from materials such as, but not limited to, glass (as a plurality of individual granules or sintered / welded breathable glass matrix or derived from a precursor of a sol-gel), quartz (as a plurality of individual granules or fused air-permeable quartz matrix), a ceramic composite containing, for example, silicon carbide (SiC), aluminum oxide (Al ₂ O ₃ ) and / or mullite (Al ₂ O ₃ -SiO ₂ ) (in the form of many individual granules or fused air-permeable ceramic matrix or breathable ceramic composite matrix), refractory polymer, for example PTFE or silicone resins (in the form of multiple individual polymer granules or breathable fused polymer matrix or derived from an emulsion template polymer foam matrix). In some embodiments, the carrier material can be liquid crystal polymer (LCP), polyetheretherketone (PEEK), Ultem, Teflon, Torlon, Amodel, polyphenylene sulfide, Forton, Xydear, Radel, Udel, polypropylene, Propylux, polysulfone, or other polymeric material.

It should be noted that the material forming the body that provides mechanical support for the plate in accordance with some embodiments (e.g., supporting plate 2304 by surrounding a hole 2303 in frame 2308 of body 2301 in FIG.1A; see below for details) is selected with some criteria. which follow the selection of the carrier material, such as the criterion for chemical acceptability, the criterion for a relatively high combustion / decomposition / melting temperature, and the criterion for low electrical conductivity. Other criteria that apply to the selection of the carrier material, such as physical integrity, uniformity and integrity, porosity and high thermal conductivity, are less important or not required for the selection of the housing material.

The amount of biologically active agent that is applied in the carrier material and / or thereon in the plate corresponds to a predetermined vaporous amount of the released biologically active agent (s) to be delivered to the lungs of the patient / user, in accordance with some embodiments, and namely, since the reservoir of the vaporous agent is a plate, it contains the agent in an amount sufficient to allow vaporization and delivery of the required vaporous and respirable amount. The amount of agent in the plate can range from 20 to 500 mg, 10 to 200 mg, 9 to 150 mg, 8 to 100 mg, 7 to 50 mg, 5 to 20 mg, 1 to 10 mg, 10 to 70 mg, 10 to 60 mg, 12 to 50 mg, 12 to 40 mg, 15 to 40 mg, 12 to 30 mg, or 12 to 25 mg.

Cartridge assembly assembly:

In some embodiments, the released biologically active agent is vaporized at a temperature requiring a significant contribution of exogenous heat in order to reach a temperature above ambient temperature. In some embodiments, the time to reach the vaporization temperature is, for example, in the range of about 1000 ms to 5 seconds, such as 250 ms, 500 ms, 1000 ms, or another greater, lesser, or intermediate value.

In some embodiments, the heating element containing the dosage unit, or cartridge, is a resistive heating element containing a metal such as nichrome, FeCrAl, cupronickel and / or stainless steel. Optionally, the heating element is packaged in thermal contact with the plate. Thermal contact includes, for example, being in direct contact or in contact through a heat transfer layer allowing a high rate of heat transfer (for example, consisting of a material with high heat conductivity such as copper, aluminum, brass or steel; and / or having a thin-walled structure, less than about 10 microns, 20 microns, 25 microns, 50 microns or other greater, lesser or intermediate thickness). In some embodiments, the thermal contact includes positioning the plate and the heating element sufficiently close together such that the plate subtends substantially the entire heat-emitting corner of the portion of the heating element covering it; for example, more than 90%, 95%, 99%, or another greater, lesser, or intermediate value. In some embodiments, the peak current supplied to the electrode ranges from about 1 to 10 amperes; for example, is approximately 1 ampere, 2 amperes, 4 amperes, 6 amperes, or other higher, lower, or intermediate current.

In some embodiments, the thermal contact comprises a heating element extending through one or more surfaces of the plate and contacting one or more surfaces of the plate, such as one side or two opposite, largest area, sides of the plate surface. In some embodiments, the thermal contact comprises a heating element that is at least partially embedded in the plate.

In some embodiments, the heating element is breathable (allows air to pass through). In some embodiments, the plate is breathable. Air permeability is ensured by conditions such as the passage of air at ambient temperature through a heated plate and heating element assembly under suction pressure (pulling force) such as suction pressure generated by inhalation and / or positive pressure generated from the opposite side of the inhalation side cartridge.

In some embodiments, the applied pressure is in the range of 4-20 mm Hg (about 5-30 mbar), 10-25 mm Hg. Art., 5-30 mm Hg. Art., 25-40 mm Hg. Art., 30-50 Hg. or another range having the same higher, lower and / or intermediate boundaries.

In some embodiments, the heating element comprises an approximately 180 degree bend such that the element is in the form of a bracket and / or a U-shape covering the plate on at least two sides. If necessary, each of the two sides of the plate is in heat conductive contact with the surface of the heating element. If necessary, the heating element on the cartridge is positioned such that there is no contact between the two sides of the U-shape. If necessary, the application of current to the heating element by the dose heating assembly is carried out in the vicinity of the two ends (containing the contact receiving regions) of the U-shape, so that heating can take place on both sides of the plate at once. In some embodiments, applying current to the heating element by connecting to the contact receiving area on either side of the plate on one or both sides of the cartridge. The heating element is additionally divided into two or more parts, each receiving current independently of each other. Alternatively, the heating element is made in one piece (optionally, a piece that completely surrounds the plate); the electrodes are applied to the contact receiving regions of the element such that a voltage potential is generated along the heating element in thermal contact with the plate.

An aspect of some embodiments relates to providing a frame along with a plate and a heating element. In some embodiments, the frame includes an opening for receiving a plate (dispensing chamber). In some embodiments, the surface area across the entire width and length of the metering chamber is in the range of about 20-100 mm ² ; for example, is approximately 25 mm ² , 50 mm ² , 66 mm ² , 80 mm ² , 100 mm ² or other larger, smaller or intermediate surface area. In some embodiments, the opening region is open on one side. Optionally, the open side of the orifice area is closed using a U-shaped heating element.

In some embodiments, the dimensions of the frame opening are, for example, about 6x10 mm, a frame defining a volume of about 1 mm thick. Optionally, the area of the hole ranges from about 20 to 100 mm ² ; for example, 20 mm ² , 40 mm ² , 50 mm ² , 60 mm ² , 80 mm ² , or it may have another larger, smaller or intermediate surface area. The hole is not necessarily square or substantially square (eg, approximately 8x8 mm); optionally, the opening has an oblong shape with an aspect ratio, for example, 1: 2, 1: 3, 1: 4, 1:10, or is characterized by another large, smaller or intermediate aspect ratio. Optionally, the hole is, for example, approximately 30x2 mm in size. In some embodiments, the opening is circular, oval, or any shape and size in a frame.

In some embodiments, the hole-containing frame performs one or more of the following functions:

• positions the plate in a reproducible position relative to the overall dimensions of the cartridge;

• provides mechanical stability to the plate (eg, supports at the edges, provides rigidity to resist bending, and / or anchors);

• provides fixing / anchoring elements and / or surfaces that allow the transfer of the cartridge by mechanical elements that are shaped to interact with the cartridge;

• provides insulation between two parallel sides of the heating element to prevent self-contact and / or

• provides a surface area and / or a volume area for attaching / anchoring / immersing a heating element with a cartridge.

In some embodiments, the general functions of the opening include shaping the dose structure during manufacture and / or assisting in the manipulation of the dose for administration.

In some embodiments, the frame comprises a polymer or ceramic that is substantially heat-resistant (eg, non-combustible, non-melting, dimensionless) at sublimation temperature. In some embodiments, the polymer comprises, for example, liquid crystal polymer (LCP), polyetheretherketone (PEEK), Ultem, Teflon, Torlon, Amodel, polyphenylene sulfide, Forton, Xydear, Radel, Udel, polypropylene, Propylux, polysulfone, or other polymeric material.

In some embodiments, the locking / anchoring member comprises a transport arm lock region shaped for attaching a dose pulling device or other dose transport mechanism to the transport arm.

In some embodiments, the plate is closed internally in the assembled cartridge by a heating element extending through the opening. In some embodiments, the heating element extends through the opening without covering the opening itself (eg, the heating tape has gaps between the turns of the tape). In some embodiments, another element is provided that acts as a security barrier (or wall). Optionally, the containment barrier is located immediately above the heating element and the plate together and / or between the heating element and the plate.

An aspect of some embodiments relates to a process for making a dosage unit, as described above, in the form of a plate and a heating element disposed within a frame.

In some embodiments, the process includes contacting a carrier material with a biologically active agent;

forming a plate containing a carrier material containing a biologically active agent introduced therein and / or applied thereto; as well as

covering the plate on at least one side with an electroresistive heating element.

As discussed above, the plate can be in the form of many separate particles or in the form of a single air-permeable matrix, and in each of these embodiments, the carrier material is contacted with the biologically active agent (s) by immersion in the carrier material, spraying with it and / or applying to the carrier material of the biologically active agent (s), or otherwise applying the biologically active agent (s) to the carrier material.

The application of the biologically active agent (s) can be carried out before, during and / or after the plate is produced. When multiple isolated biologically active agents are applied, they can be applied simultaneously and / or sequentially.

Application of the biologically active agent (s) can be carried out, for example, using a liquid form of the biologically active agent, either as an isolated (pure) liquid, or as a solution of the biologically active agent, which can be a dissolved liquid or a dissolved solid. When using a solution of biologically active agent (s), the process may further include drying the solvent of the solution so as to leave a coating of the isolated biologically active agent in the carrier material and / or on it or part of it.

In some embodiments, a process for forming a plate made of a plurality of particles includes placing a plurality of particles of carrier material having the selected biologically active agent (s) incorporated therein and / or applied thereto in a dispensing chamber on a flat surface;

vibrating a flat surface until many particles are aligned; as well as

pressing an aligned plurality of particles so as to form a plate.

In some embodiments, the process of forming a plate made of a single breathable matrix includes cutting a section from a carrier material to form a single breathable matrix. In embodiments where the carrier material is cut from a larger piece of material, the biologically active agent (s) may be applied thereto before or after cutting the material.

In some embodiments, a process for forming a plate made from a single breathable matrix includes pressing a plurality of particles of carrier material into a shape having an inverse final plate shape so as to combine the particles into an air-permeable matrix, while such a process may be referred to as fusion or sintering. In such cases, the application of the biologically active agent (s) is carried out after the pressing step.

In some embodiments, a measured amount of particles of a carrier material containing a measured amount of an isolated biologically active agent applied thereto, referred to as a loaded carrier material, is placed in a dispensing chamber. In some embodiments, the measured amount of loaded carrier material is in the range of, for example, about 1-100 mg. In some embodiments, the metering chamber is calibrated such that the size of the plate, when formed, is limited by the boundaries of the metering chamber, such as the width and length of the plate.

In some embodiments, the measured amount of loaded carrier material is balanced by vibration of the metering chamber. If necessary, vibration occurs with an amplitude in the range of approximately 0.1-1.2 mm; for example 0.5 mm. The vibration frequency, for example, is in the range of approximately 20-300 Hz (for example, 30 Hz, 45 Hz, 60 Hz, 75 Hz, or another higher, lower or intermediate frequency). The shaking duration, for example, is selected from the range of 100-1100 ms (eg, approximately 300 ms, 400 ms, 500 ms, 800 ms, or other longer, shorter or intermediate times). Optionally, the chamber is secured to vibration to prevent the loaded carrier material from escaping from the bottom of the chamber.

In some embodiments, the plate is formed from the aligned loaded carrier material by compression with a compression member. In some embodiments, the loaded carrier material is compressed to a plate with a thickness in the range of about 200-1500 microns, or a thickness within another range, characterized by the same, large, smaller and / or intermediate boundaries.

"Empty" dosing unit:

An aspect of some embodiments relates to providing the frame with the plate and optionally also with the heating element without the biologically active agent included therein. In some embodiments, the dosage unit is prepared essentially as described herein separately for applying a biologically active agent intravenously to a dosage unit plate. After the biologically active agent is placed on / on the plate of such an “empty” dosage unit, the “filled” dosage unit can be used for pulmonary delivery of the biologically active agent, essentially as described herein.

In some embodiments, an empty dosage unit can be filled, for example, by directing a spray or dripping onto a plate in the dosage unit. If necessary, this is done when removing the heating element or before attaching it. In some embodiments, the biologically active agent is applied throughout the dosage unit, including the heating element and / or frame. If necessary, in such cases the frame (and possibly also the heating element) is made of or contains materials that can repel the active agent in wet and / or dry form or otherwise have a low tendency to maintain contact with it.

In some embodiments, an empty dosage unit can be filled by removing the plate from the frame of the dosage unit, applying the released biologically active agent to and / or into the plate, as described herein, and reattaching the plate to the frame. If necessary, the plate is separated from the heating element so as not to apply the biologically active agent to the heating element when applying the biologically active agent i / on the plate.

Dosing unit nebulization device and activation:

An aspect of some embodiments relates to the positioning and activation of a dosage unit carrying a plate with an integrated heating element inside the chamber that activates the heating element while retaining the vaporized released biologically active agent in the substance delivery channel, and thus relates to an activating unit for positioning and activating the dosage unit.

In some embodiments, positioning is accomplished by moving the cartridge along a track (eg, using a cartridge transport mechanism). In some embodiments, the chamber comprises a structure that surrounds the cartridge on both sides to close it within a certain lumen and provides electrical contact with the cartridge heating element. Optionally, electrical contact is located on both sides of the cartridge. Optionally, electrical contact is made on the sides of the cartridge at points determined by positioning the cartridge relative to the electrodes of the vaporizer. Optionally, contact pads extend from the heating element to make electrical contact with it.

An aspect of some embodiments relates to a cartridge container for use with a substance vaporizer, which alternately:

• attached to the container of the cartridge for receiving the dosage unit (cartridge) into the substance evaporator; as well as

• detaches from the dose cartridge container.

In some embodiments, a removable substance vaporizer is used as part of an interlock mechanism to control atomization of dosage units. For example, in some embodiments, a substance vaporizer is used as part of a lockout activation that prevents a new dosage unit from being removed until a previously spent cartridge is returned to the dispensing container.

Illustration of several examples:

Various examples of embodiments of the listed elements are described herein, as well as examples of embodiments of assembled dosage units that do not contain at least one of these elements. It should be understood that the various element embodiments are optionally also combined into assembled dosage unit embodiments in other combinations (eg, any heating element design is provided with any frame design).

FIG. 1A-B are schematic views of a dispensing unit 2300 (evaporative substance dispensing cartridge) disassembled and assembled in accordance with some embodiments. Reference is also made to FIG. 1C-M, which schematically illustrate alternative designs of dosage units 2350, 2360, 2370, 2380, 2390, and 2395, in accordance with some embodiments. FIG. 1C, 1E, 1G, 1J and 1L show disassembled dosage units, while FIG. 1D, 1F, 1H, 1K, and 1M show the assembled dosage units.

In some embodiments, the doses of the isolated biologically active agent are collected on and / or within the 2300 dosage unit. Optionally, dosage unit 2300 contains:

a plate 2304, optionally formed by, for example, flattening for rapid evaporation;

mechanical support for the plate 2304 (eg, support by fencing within the opening 2303 in the frame 2308 of the housing 2301, which is not necessarily in the form of a frame);

means for facilitating transport of the dosage unit 2300 (eg, jaw latch 2302); and / or

means for vaporizing the plate 2304 (eg, resistive heating element 2306).

Optionally, the dosage unit is disposable. Potential benefits of a disposable dosage unit include: retention of active disposal residue; tight integration of support and transport of the dosage for reliable dosed transport within the dosing apparatus; and / or a reduced need to maintain and / or monitor portions of the dispensing system (eg, an evaporative heating element) that are exposed to conditions that can result in decreased performance over time.

Optionally, the dosage unit is used for use in a single inhalation. Potential advantages of a single-use dosage unit include improved accuracy and / or reliability in adjusting the vaporous amount of the biologically active agent, in accordance with the settings of the inhaler.

For example, the concentration and / or dispersion of the recovered biologically active agent into the loaded carrier material can be controlled during manufacture to some degree of precision. In general, the rate of change in device output (eg, the amount of vapor and respirable biologically active agent) can be kept within tolerance at less than +/- 15% of the intended yield. Other factors that can influence the differences in device output include environmental conditions, the user's usage habits, and the user's current state.

In some embodiments, dosage unit 2300 includes a housing 2301 containing an opening or receiving chamber 2303. Optionally, housing 2301 includes a flattened and elongated strip, while receiving chamber 2303 includes a strip-framed opening (frame 2308). During preparation of the dosage unit 2300, the plate 2304 is inserted into the receiving chamber 2303. Optionally, the plate is shaped before or during insertion so that it conforms to the flattened shape of the receiving chamber 2303. A potential advantage for the plate 2304 is to be in a flattened shape because surface area and / or uniform thickness potentially allows for faster and / or more even distribution of heat and / or airflow during evaporation and delivery.

In some embodiments, the dimensions of the plate are, for example, about 6x10 mm over the entire exposed surface area, and also about 1 mm thick. Optionally, the thickness of the plate is in the range of about 0.1 to 1.0 mm, or it can be greater, less or intermediate thickness. Optionally, the surface area of the plate ranges from about 20 to 100 mm ² ; for example, 20 mm ² , 40 mm ² , 50 mm ² , 60 mm ² , 80 mm ^2, or it can have another larger, smaller or intermediate surface area. The plate is not necessarily square or substantially square (eg, approximately 8x8x1 mm); optionally, the plate has an elongated shape with an aspect ratio, for example, 1: 2, 1: 3, 1: 4, 1:10, or is characterized by another large, smaller or intermediate aspect ratio. Optionally, the plate is, for example, about 30x2x0.5 mm in size. The corresponding plate is about 15 mg by weight in some embodiments. In some embodiments, the weight of the plate is selected from about 1 mg to 100 mg, or another range with the same, larger, smaller, and / or intermediate ranges.

A potential advantage is that the plate 2304 is surrounded by a housing with a frame 2301 for greater mechanical stability. For example, plate 2304 potentially contains discrete particles of loaded carrier material, such that plate 2304 is susceptible to particle shedding, especially when moved or flexed. The enclosure of the cartridge frame 2308 allows the plate 2304 to move in the system without applying stress directly to the plate 2304 itself. In some embodiments, the total length and width of the cartridge is approximately 20x10 mm, or other larger, smaller, or intermediate sizes. In the manufacturing process, a bezel housing is a potential advantage for forming a plate of the right size to fit the bore through which volatiles released during the heating of the plate are entrained with the air flow.

It should be understood that complete surroundings of the wafer are not required, in some embodiments, to achieve sufficient mechanical stability. For example, in some embodiments (see, for example, FIGS. 1E-F) a plate 2304 is placed in an open on one side chamber 2363, defined as an "and" -shaped portion of frame 2361. This potentially allows the plate 2304 to be packaged in a dispensing unit 2360 from the open side of a portion of the frame 2361. Potentially, the "and" -shaped frame simplifies and / or accelerates the formation and / or release of the frame itself during production. In some embodiments, the open side is closed by, for example, a structure such as a resistive heating element 2306, a permeable patch 2375 (optionally a retention mesh; FIG. 1G), or other structure.

In some embodiments, other types of plate support are provided. A completely bezel-less example is shown, for example, in dispensing unit 2390A in FIG. 1L, where the entire extent of the frame 2391A (optionally including even the jaw-shaped latches 2392) is provided by the plate material. In some embodiments, the plate material is sufficiently stable after preparation so that no or relatively little additional mechanical support is required for use (eg, the plate is compressed so that it remains unchanged during transport between the magazine and the clamping chamber). Optionally, at least a portion of the plate material is mixed with a binder to add stability. Optionally, the plate is a solid plate with sufficient stability and serves to hold a gel, liquid or powder containing the active agent (s).

In some embodiments, a one-piece plate / frame is formed, optionally with a variety of plate materials, such as a frame material for the frame region 2391A (which may or may not contain an active agent), and a carrier material containing an active agent to release in the area of the 2394A plate. Optionally, a one-piece plate / frame is formed from one material, but the active agent (s) is added thereto only in the region of the plate 2394A. Additionally or alternatively, the formation conditions (eg, the degree of compression packing) differ between the frame portion of the wafer and the biologically active substance releasing the portion of the wafer. In some embodiments, the carrier material covers, for example, about 60 mm ² near the center of the 2393 plate. The carrier material is an active agent material that is positioned in a dispensing unit in combination with a heating element so that it can be heated. In some embodiments, heating element 2306 also provides mechanical support. Optionally, the plate / frame assembly 2393 in turn provides electrical insulation between portions of the heating element 2306. Contact between the heating element 2306 and the plate 2393 is made, for example, using any method known in the art that will remain stable throughout use time, including, for example, one or more of welding, glue, cold press, hot press, and / or pins.

In some embodiments (eg, dosage unit 2395 in FIG. 1M), plate 2399 is provided with perforations 2398 that increase its flow permeability. This represents a particular potential benefit for bezel-less or near-bezel-less dosage unit embodiments. Plate 2399 of dispensing unit 2395, for example, is limited only by jaw latches 2396 (which can be formed as an integral part of the plate) and (transparently drawn) "and" -shaped heating element 2306. Potentially, a carrier material with sufficient density to achieve mechanical intrinsic stability reduces the permeability to the air flow of the resulting plate, thereby preventing the volatilization of drugs. Perforations 2398 are provided, for example, by inserting gaps with a tool (mold, for example) used in packaging the carrier material, by perforating the plate after formation, or otherwise.

In some embodiments (dosage unit 2390 in FIGS. 1J-K), jaw latches 2391 are provided as a separate piece (eg, made of polymer or metal) attached to a plate 2394 of carrier material containing the release active agent. In some embodiments, a heating element 2306 or other wrapping structure provides additional mechanical support. Optionally, attaching the 2394 plate to the 2391 snap jaws involves the use of adhesion. Optionally, the connection includes mechanical connection; for example, one of the latches 2391 and the plate 2394 are formed with a tongue and the other with a slot, and / or the latches 2391 are provided with protrusions (for example, a ridge of tenons) around which the plate 2394 is formed.

In some embodiments (eg, cross-sectional view of metering unit 2380 shown in FIG. 1I), a heating element 2386 that encloses plate 2304 is welded to an assembly 2381 where two sides of the heating element converge. This is potentially an advantage to provide additional mechanical stability to the plate 2304 (and in particular for one of the frameless or partially frameless embodiments). Since weld 2381 alters the electrically conductive topology of heating element 2386, electrodes 2331 for providing thermal energy to heating element 2386 are optionally placed on opposite sides of the heating element (optionally, but not necessarily in contact with the region of the weld 2381 itself).

In some embodiments, vaporizing the recovered biologically active agent comprises heating with resistance heating element 2306 or other form of resistance heating element. The resistive mesh further comprises a material that exhibits significant resistive heating; e.g. nichrome (typical resistance is approximately 1-1.5 μΩ⋅hm), FeCrAl (typical resistance is approximately 1.45 μΩ⋅hm), stainless steel (typical resistance is approximately 10-100 μΩ⋅hm) and / or cupronickel (Typical resistance is approximately 19-50 μΩ⋅Ω). According to the choice of material (e.g. metal), parameters such as length and width, thickness, size and / or pattern of the holes of the heating element are adjusted to have a total resistance across the resistance heating element, which, for example, is in the range of about 0, 05-1 Ohm, 0.5-2 Ohm, 0.1-3 Ohm, 2-4 Ohm or in another range that has the same, above, below and / or intermediate boundaries.

Optionally, during assembly, the resistance heating element 2306 is attached to the body 2301 in a position that overlaps the plate 2304 on one or more sides. For example, resistance heating element 2306 extends over dorsal surface 2309A, folds at the end of housing 2311, and extends rearwardly along ventral surface 2309 V. Optionally, resistance heating element 2306 extends around chamber 2303 such that plate 2304 contained in chamber 2303 is obscured by heating element 2306. In some embodiments, resistive heating element 2306 comprises a plurality of discrete panels, such as panels 2356 and 2356A in FIG. 1C-D, one on each side of the 2350 Dispensing Unit. Optionally, the panels are electrically connected to one another. Alternatively, each receives separate electrical connections. A potential advantage of multiple and separate panels for a resistance heating element is the ability to perform controlled vaporization in preselected areas of the plate. A potential advantage of the double-sided enclosure of the body of the plate 2304 (used in some embodiments) is to increase the rate and / or uniformity of vaporization when current is applied to the heating element 2306. In some embodiments, only one fence panel 2356 is an electrically resistive element and the other panel 2356A optionally is a mesh or other breathable structure (eg, a porous structure) that provides mechanical support.

In some embodiments, the electrical resistance heating elements 2356, 2356A operate simultaneously. In some embodiments, the resistive heating elements operate separately. This is a potential advantage, for example, to be able to separately control and / or release two different agents and / or one agent in two successive deliveries. For example, the first heating element (panel, for example) operates with sufficient energy to vaporize the medium immediately below it, but for a short enough time or with such a heating profile that heat does not pass completely through the plate. With some offset in time (optionally overlapping or completely separated from the first heating), the second heating element operates. This is potentially an advantage when two substances with different volatilization properties are to be released depending on time or temperature (for example from two different plate materials). Optionally, the two heating profiles are adjusted to result in simultaneous vaporization. Additionally or alternatively, the evaporation of the two agents is deliberately time-shifted. For example, a plate containing a perfume or concealer is placed in the plate near a heating element where it evaporates first and the second evaporates shortly thereafter (or vice versa). This is a potential advantage, for example, to mask a potentially unpleasant taste to signal the user that a vaporization state is in progress, and / or otherwise modify the sensory experience of inhalation. Optionally, each electrode is heated on an entire side of the plate. Alternatively, each heating element is designed such that heating for vaporization occurs only through a part of the plate, possibly in a different part for each electrode. In some embodiments, one heating element is used to "preheat" the plate to a threshold below the release of the active agent, and the second heating element is actuated to achieve the release itself. Potentially, preheating followed by heating to release will shorten the vaporization period of the agent and / or increase the concentration after release. Potentially, this helps to increase the amount of agent reaching the lungs and / or targeted release to a narrower selected respiratory depth.

In some embodiments, resistive mesh 2306 has an open (hole) to closed (mesh) surface area ratio of about 1: 1 (50%) to 1: 3 (33%). In some embodiments, the ratio is in the range of about 10-20%, about 20-40%, about 30-50%, about 40-70%, about 60-80%, about 70-90%, or another range of ratios having the same, large, smaller and / or intermediate boundaries. In some embodiments, the mesh openings are in the range of about 10 microns, about 25 microns, 32 microns, 50 microns, 75 microns, 100 microns, 200 microns, 300-750 microns, 700-1200 microns, or another larger, smaller, or intermediate range. Optionally, the at least two holes are of different sizes and / or shapes. In some embodiments, the mesh is a 400 / 0.03 316 stainless steel mesh with 0.033 mm apertures, 400 holes per square inch, each hole being approximately 0.033 mm (33 microns), 0.03 mm thick wire.

In some embodiments, at least one heating element 2306 is fully or partially embedded in the plate 2304. Optionally, the heating element 2306 is partially or completely embedded in the frame of the housing 2301. For example, the housing 2301 is initially molded with the heating element and / or heating element in place. 2306 is pressed into place at a high temperature in a different manufacturing step. Optionally, a plurality of heating elements 2306 are incorporated in whole or in part into the plate 2304 so that they can operate simultaneously or separately.

FIG. 1G-H illustrates another embodiment of a dispensing unit 2370 including an immersed heating element 2376 in a frame 2371. In some embodiments, a heating element 2376 includes a heating section 2378 disposed between a plurality of electrode pads 2377. In an assembled dispensing unit, the heating section 2378 extends across or in chambers 2303 and across or across plate 2304. For example, plate 2304 is optionally formed by pressing bulk material into place around heating element 2376, immersing it. Optionally, frame 2371 includes one or more recesses 2377A that receive electrode pads 2377. In some embodiments, additional mechanical support for the plate is provided by a permeable overlay 2375 extending at least one side of dosage unit frame 2371. Overlap 2375 optionally comprises a polymer mesh or another structure to provide gas flow.

In some embodiments, the heating section 2378 of the heating element 2376 is a wire that traverses the chamber 2303 one or more times when connected to the electrode pads 2377. In some embodiments, the heating section 2378 comprises a mesh, tape, or other shape. In some embodiments, the heating section 2378 is divided into a plurality of discrete portions (branches, layers, or other subdivisions). In some embodiments, the heating section 2378 extends adjacent (eg, within 1 mm, within 2 mm, or another greater or lesser distance) with substantially all portions of the drug release plate. This is a potential advantage to obtain a faster and / or more uniform release of the substance when heated.

It should be understood that although the electrode contacts 2377 are electrically separated from each other, except as they are attached to the heating section 2378, they should not be placed at physical distance from each other, depending, for example, on the course (s) passing the heating section 2378 by itself. Optionally, the electrode contacts are located on the same or on different sides of the chamber 2303, for example.

In some embodiments, resistive heating element 2306 comprises resistive foil (eg, foil stretched into a continuous tape or other shape supported by a polymer such as polyimide and / or silicone rubber). Optionally, the supported resistive foil is perforated through the backing to allow air to escape while the dispensing material is volatilized. In some embodiments, an igniter is added to the resistive foil, for example, as an additional component and / or as a region of the tape made intentionally thin, so as to provide a method for destroying the heating element after use (by conducting an appropriate high current through the heating element for a sufficient period of time).

In some embodiments, the resistance heating element 2306 is attached to the body of the cartridge 2301 by pressing the mesh on the body using a temperature high enough to melt the body and / or soften so that the mesh sinks into the body material. In some embodiments, the housing comprises an inert, heat resistant, suitable material. In some embodiments, the housing material used comprises, for example, liquid crystal polymer (LCP), polyetheretherketone (PEEK), Ultem, Teflon, Torlon, Amodel, polyphenylene sulfide, Forton, Xydear, Radel, Udel, polypropylene, Propylux, polysulfone, or other polymeric material.

A potential advantage of LCP and / or PEEK is good resistance to temperatures above the temperature required to vaporize the substance supported in the cartridge. In some embodiments, attachment of the mesh and body occurs at a temperature of about 280 ° C (or another temperature high enough to melt and / or soften the LCP or PEEK). LCP and PEEK provide the potential advantage of good thermal stability at lower temperatures, for example at an evaporation temperature of about 230 ° C.

A potential advantage of providing a heating element, such as resistance heating element 2306, to each individual dosage unit is to ensure uniform performance between uses. Potentially, a portion of the biologically active agent with which the heating element comes into contact remains adhered to the heating element after cooling. This build-up can potentially affect vaporization performance. Remote heating (via radiation and / or indirect conduction, for example) potentially creates a system having relatively high thermal inertia (more heating power required) compared to direct conductive heating using a contact electrode; the problem of contamination of the contact electrode is removed by designing it for one-time use. The reduced heating requirement potentially improves the safety and / or longevity of the device. Potentially, the reduced heating requirement also reduces power delivery requirements, allowing embodiments with increased portability, longer charge life, and / or reduced cost (eg, for battery-powered heating element systems).

In some embodiments, dosage unit 2300 includes a locking member for use in transporting the dosage unit. The locking element comprises, for example, a jaw-shaped latch 2302. The locking allows one or more suitable transport elements of the dispensing system to engage and / or move the dispensing unit. Moving and / or securing a batching unit from unwanted movement can occur during the service cycle of a batching unit, for example: when a batching unit is placed in a queue of batching units containing a plurality of batching units organized for use, when a batching unit advances in the queue, when a batching unit is selected for use when the metering unit moves to the position for use when the metering unit is actually in use and / or when the metering unit is discarded or alternatively moves to a "used" position in the metering unit queue.

Carousel and Evaporator:

FIG. 2A-E schematically illustrate a carousel-type dose delivery system 2340 for use as part of an inhalation device, or even an MDI device, in accordance with some embodiments.

In some embodiments, the dose delivery system 2340 includes a carousel 2322 holding a plurality of dispensing units 2300 enclosed in a housing 2324 and an evaporator 2321 containing a dose drawer 2314 and a clamping chamber apparatus 2320. The carousel 2324 body and evaporator 2321 are attached to each other. to friend; the carousel 2322 rotates to represent the dosing units to the evaporator 2321 in the order they are loaded or in another order as the carousel 2322 operates.

Optionally, the 2324 carousel body (and its contents) is replaceable for a new body assembly, for example, when some or all of the dosage units are consumed, expire, or need to be replaced to change the dosage unit composition. The number of dosage units carried in the housing is, for example, about 100. If desired, the number of dosage units is another number in the range of 10-200 (for example, 10, 40, 80, 120, 180 or 200) or another higher or lower number ... In some embodiments, the diameter of the carousel is, for example, in the range of about 7-10 cm, or larger or smaller, in accordance with, for example, the number and size of dosage units to be placed. Optionally, the carousel 2322 contains the same dosage units or many different dosage units (eg, containing different amounts, concentrations, and / or isolated biologically active agent compositions). It should be understood that the carousel is not the only form of cartridge storage that can be used with dosage units. For example, the dosage units can be stored in a spring-loaded, magazine-like storage system. A potential advantage of the carousel is the free (rather than strictly sequential) access during loading and / or unloading to the positions of the dosage units; for example, to adjust the dosage regimen. Other potential benefits of using a carousel relate to secured storage, abuse control, security, and other regulatory requirements and props.

In an exemplary work cycle, dose withdrawal 2314 extends from evaporator into rotary housing 2324 where it attaches to dispensing unit 2300, such as by a jaw latch 2302. In some embodiments, dose withdrawal 2314 "snaps" onto location within the latches-jaws 2302. In some embodiments, the dose withdrawal tool 2314 comprises two portions that move laterally on opposite sides and then close together within the space defined by the jaws 2302 (potential application of a lower force to jaws 2302 and / or dispensing unit 2300 than snapping-by-insertion method). Further action pulls back into the evaporator the actuator and the dosing unit 2300 attached to it. The dosing unit load 2304 of the dosing unit 2300 is thus pulled along with the air inlet 2312. It will be appreciated that the dose withdrawal device is potentially operating in a different hand action of the transport: for example, as a "pusher" of the dose (containing, for example, a spring loaded element in the carousel itself) and / or a magnet (in pull mode) or magnets (in push or pull mode).

In some embodiments, gripping members 2310A and 2310B are positioned close to the cartridge, bringing the electrodes in place to heat the dispensing agent to vaporize volatiles therefrom.

FIG. 3A-B schematically depict a clamping chamber apparatus 2320 for vaporizing and delivering an isolated biologically active agent from dosage unit 2300, in accordance with some embodiments.

The dosage unit 2300 is transported into the clamping chamber apparatus 2320, for example, by moving the dose pulling tool 2314 while engaging with the jaw latch 2302.

In some embodiments, the clamping chamber apparatus 2320 (also referred to as a vaporizer) is composed of two clamping members 2310A, 2310B that engage the dosing unit 2300 upon vaporization. In some embodiments, each terminal 2310A, 2310B carries a corresponding electrode 2330A, 2330B that is positioned to be pressed into contact with resistive heating element 2306 or other heating element that form part of dispensing unit 2300. Electrodes 2330A, 2330B, in turn are in electrical contact with the power source. Heating is accomplished, in some embodiments, by switching current through electrodes 2330A, 2330B, through resistive heating element 2306. Electrodes 2330A, 2330B are positioned such that current follows a path extending substantially over at least one side (two to the sides in the illustrated example) of the charge of the dosing substance, so that heat can be evenly distributed over the surface of the charge 2304 and applied thereto.

In some embodiments, air flow passes through the air inlet 2312, through the heated plate 2304, and exits through the outlet 2312B. Optionally, the outlet 2312B is in fluid communication with a tube that is guided to deliver the vapor to the user. Optionally, the clamp members 2310A, 2310B include portions of the air inlet 2312 and the outlet 2312B. This potentially allows the gripping members 2310A, 2310B to alternately open to obtain the dosage unit 2300, and also to close to seal the air passage around the dosage unit 2300, so that the vaporous released biologically active agent (s) is confined to a specific channel.

Upon delivery of the dose, ejecting the dispensing unit comprises disengaging the dose drawer 2314 from the latch-jaw 2302; for example, by moving one of the two parts while restraining the other and / or deforming one of the two parts. For example, the drawer 2314 is further retracted while the dispensing unit 2300 is prevented from following it by limiting the size of the slot through which it moves. In some embodiments, release is followed by ejection: for example, the dispense unit is dropped from its seat, pushed by the returning action of the dose drawer 2314, and / or otherwise transported out of the device as a whole. In some embodiments, the dosage unit is returned to the carousel 2322 as the dose used (in the same or a different available slot other than the one from which it was retrieved). Optionally, this is done after a short time or immediately after the end of use. Alternatively, the dosing unit is thrown into the frame of the next use of the device, in which case the carousel also advances, representing the next dosing unit to be used.

In some embodiments, the doses loaded into the carousel are accessed sequentially in the order they are loaded. In some embodiments, the dispensing order is predetermined but varies, for example, dispensing different amounts to be administered over a period of time are arranged in the order that the carousel is loaded. In some embodiments, the carousel movement (advancement) is substantially in accordance with a sequence of actions that are mechanically coupled to dose-pulling and / or dose-returning actions. In some embodiments, the movement of the carousel is controlled by a controller, such as a microprocessor-controlled stepper motor or other advancement mechanism. Optionally, the controller controls the dose that is in the cartridge slot and / or its status. Optionally, the controller automatically and / or on command selects the appropriate dosage unit and moves it into position in as many steps as necessary to make it drawable. Optionally, this selection allows out-of-order access to the dosing unit in the carousel. Optionally, the carousel is promoted as a result of user actuation of the device. Removable Evaporation and Delivery Device:

FIG. 4A-B schematically illustrate an inhalation device for loading from a carousel and separable from the carousel for vaporizing and delivering an isolated biologically active agent from a dosage unit, in accordance with some embodiments.

In some embodiments, the functions performed by the clamping chamber apparatus 2320 are performed in detachable portions such that the gripping / heating / insertion assembly is separable from the portions of the stored dose pulling and transporting assembly, at least to deliver a dose to a user. In some embodiments, grip / heating / insertion assembly 2400 comprises a substantially cylindrical body (eg, in the form of a cigarette, cigarillo, cigar, and / or pen) that fits into the container of the dose draw and transport assembly. Node 2400 includes a slide mechanism 2410 or other structure that is included in the transport node and / or activated by manual or other external operation.

Optionally, slider mechanism 2410 slides out of inlet end 2440 of assembly 2400 to engage metering unit 2300 with connection portion 2415, as described, for example, in connection with dose withdrawal device 2314. Optionally, metering unit 2300 (formed, for example, with a long and narrow plate 2404) is pulled into the clamping / heating unit. The clamping / heating assembly optionally comprises electrodes 2430 that are loaded with spring elements 2407 or other means for pressing the resistance heating element 2306 to provide electrical contact therewith. Optionally, heating power is provided by battery 2413 connected to electrodes 2430 via wires 2414.

Optionally, the battery 2413 is rechargeable, for example, the battery 2413 is rechargeable from a source provided by the main body assembled with the carousel. Optionally, heating starts after operation of a control (e.g. a button) and / or is subjected to one or more automatic activations, modulations and / or blocking controls such as heating when sensing a pressure change and / or opening an air shunt to control speed and / or quantity delivery of the dose. During delivery, air is drawn through the body 2420 (e.g., orally by inhalation) by applying suction to the end 2450. Air drawn into the inlet end 2440 is forced by the baffles / conduits 2401, 2408 to pass through the heated plate 2404 carrying the vaporous biologically active means by the end of 2450.

A potential advantage of the split design is the reduced force required by the user to operate the dispensing device during dose delivery. Another potential advantage is the separation of dose selection, administration and control functions from dosing itself. There is a potential positive psychological effect by separating the dosing act that approximates a normal e-cigarette from the more clinical aspects of dosing control.

In some embodiments, the removable dosage unit comprises a plurality of separately heated regions; for example, material is loaded into various holes and / or the hole is crossed by a plurality of separately available heating elements. Optionally, different downloads contain different isolated biologically active agents. For example, a cannabis load is not necessarily followed by one or more isolated cannabinoid downloads, such as THC isolate, and / or various cannabinoid downloads, such as isolated CBD.

In some embodiments, analog and / or digital circuit logic is used to control which area of the heating element receives current. For example, each heating element is not necessarily intentionally "burnt" (by breaking a fuse, for example) after use. An appropriately organized control circuit detects the first unused dosing area and selects it for the next activation. The potential benefit of this is to allow the dosage to be spread over multiple breaths. Another potential advantage is the ability to dosing for one purpose (eg, medical) to be combined with dosing for other purposes (eg, alternative medical purposes, or to allow access to additional inhalations for recreational purposes). Another potential advantage is the ability to use several types of doses (eg, compositions of various isolated biologically active agents) for the purpose of adding variety to the user experience.

FIG. 5 is a schematic diagram of an interlocked dose nebulizer 2500 along with a removable dose delivery assembly 2400, in accordance with some embodiments.

In some embodiments, nebulizer 2500 includes a plurality of receiving ports 2501, 2502 for delivery assembly 2400. In some embodiments, port 2501 is an opening from which an unused dosage unit 2300C, 2300A is retrieved into delivery assembly 2400. In some embodiments, after Once the 2300A dosing unit is removed from the 2500 nebulizer, the next 2300C dosing unit is not advanced to the desired position until the lockout conditions are met. In some embodiments, operation of the locking device includes inserting an insertion assembly 2500 into an opening 2502. Optionally, the insertion triggers (eg, mechanically and / or controller-activated operation) movement of the carousel such that dispensing unit 2300C moves into position. In some embodiments, inserting (optionally inserting and removing) the delivery unit 2400 retrieves the dispensing unit 2300A, which is now in the same position as the used dispensing unit 2400B. Potentially, this latching mechanism helps to ensure that only one dispense unit is removed from the nebulizer 2500 at the same time. In some embodiments, the carousel does not advance unless the dispense unit 2300A is defined within the insertion assembly 2400 when inserted into the opening 2502. According to some In embodiments, dispensing unit 2300A is inserted into delivery unit 2400 such that it cannot be removed without destroying dispensing unit 2300A and / or delivery unit 2400.

Inhalation device:

A dosage unit comprising a plate of one or more isolated biologically active agents disposed on top of a carrier material and configured to be vaporized by a heating element in accordance with some embodiments may be used in an inhalation device configured to conduct electrical current through the heating element and allowing air to pass through the heated plate to carry the vaporous agent into the lungs of the patient or user. An inhalation device using a dosage unit as provided herein may be a metered dose inhalation (MDI) device.

In some embodiments, the inhalation device is configured for precise dosage suitable for medical purposes. An accurate dosage can be achieved using a previously measured amount of biologically active agent (s) and / or by controlling the heating profile (e.g., temperature and / or heating rate, and / or duration) used for vaporization and / or flow profile (e.g. flow rate and / or changes in flow rate and / or duration). In some embodiments, the device is configured for general vaporization of the biologically active agent (s) with low accuracy requirements.

In some embodiments, the inhalation device comprises at least one dosage unit as described herein, and further comprises an activation unit configured to move the dosage unit from a storage position to an operating position and actuate the passage of current through the heating element as described above.

In accordance with some embodiments, the inhalation device further comprises a dosage unit nebulization apparatus that includes a plurality of dosage units.

In accordance with some embodiments, the inhalation device further comprises a clamp chamber apparatus (also known as a vaporizer) as described above.

In accordance with some embodiments, the inhalation device is essentially an MDI device as described in WO 2012/085919 and / or any of US Provisional Patent Applications 62/035588, 62/085772 and 62/086208. including any of the embodiments described therein and any combinations thereof.

In accordance with one aspect of some embodiments, there is provided an MDI device configured to pulmonarily deliver a predetermined vaporous amount of at least one biologically active agent (pharmacologically active agent) to a patient, the agent being an isolated biologically active agent, and:

the device is configured to deliver said predetermined vaporous amount of the agent under controlled heating of the plate containing the agent;

a predetermined vaporous amount is selected to provide a preselected pharmacokinetic profile and / or a preselected pharmacodynamic profile of the agent in the patient; as well as

a predetermined vaporous amount is obtained by measuring at least one pharmacokinetic (PK) parameter and / or at least one pharmacodynamic (PD) parameter induced by pulmonary delivery of an agent to a patient from an MDI device (PK / PD studies). Such PK / PD parameters are generally known in the art and are discussed herein below, and can be measured or estimated according to well known methods, referred to herein as PK / PD studies.

In accordance with some embodiments, the MDI device is configured to communicate with an electronic patient interface unit and integrate into a system designed to provide PK and / or PD (PK / PD) data collection and entry, patient record storage, automatic or manual calibration, adjusting, resetting, and redefining the initial device preset by the patient and / or clinician, as will be detailed later herein.

The variability of PK / PD among a patient cohort is particularly low for some isolated biologically active agents, and can be achieved through the use of an accurate and consistent MDI device, in accordance with some embodiments of the present disclosure.

In accordance with some embodiments, the methods and devices provided herein are also characterized by high accuracy, consistency, correctness and reproducibility of results, which is expressed by the minimum deviation between the actual vaporized amount of the agent inhaled by the patient and the predetermined vapor amount of the agent.

In accordance with some embodiments, an inhalation device for controlled evaporation of at least one active pharmaceutically active agent from at least one kind of substance by applying heat includes:

at least one dosage unit (cartridge) containing a plate that contains at least one isolated biologically active (pharmaceutically active) agent;

a heating element adapted to apply heat to the plate to vaporize a pharmaceutically active agent; as well as

a mechanism adapted to move the cartridge relative to the controller to power the heating element.

In accordance with some embodiments, the inhalation device is configured to controlled evaporation of at least one active pharmaceutically active agent from at least one kind of substance by applying heat and air flow and, accordingly, also includes a mechanism adapted to control the air flow through the plate.

In some embodiments, the device further comprises a plurality of dispensing units disposed in a belt, garland (carousel), or store. Optionally or additionally, the plate is organized with a predetermined amount of pharmaceutically active agent per unit area of the plate in each dosage unit in a tape, garland, or store.

Optionally or additionally, the thickness of the dosage unit ranges from about 0.1 mm to about 2.0 mm. Optionally or additionally, the tape, carousel, or magazine contains a total of about 5 grams to about 100 grams of loaded plates. Optionally or additionally, the tape, carousel or store contains a sufficient amount of active pharmaceutically active agent for at least two exposures. Optionally or additionally, the cartridge comprises a first layer of material bonded to the plate, a first layer containing holes large enough to allow evacuation of gases, but small enough to contain heated plate material. Optionally or additionally, the diameter of the holes is 25 µm to 500 µm. Optionally or additionally, the cartridge comprises a second layer of material bonded to the plate, and the second layer is configured to transfer heat to the plate without substantially distributing heat over the second layer. Optionally or additionally, the heating element and the plate are held between the first and second layers.

In some embodiments, the device further comprises an inhalation unit comprising a mouthpiece for inhaling a pharmaceutically active agent, the mouthpiece being in fluid communication with a vaporization chamber of the device, the vaporization chamber containing a vaporous active pharmaceutically active agent.

Optionally, the mouthpiece contains a one-way valve for controlling the flow of liquid from the vaporization chamber. Optionally or additionally, the device further comprises a sensor in fluid communication with the mouthpiece, the sensor being adapted to estimate the air flow rate and sending a signal to a controller adapted to vaporize the pharmaceutically active agent in accordance with the air flow rate.

In some embodiments, the device further comprises a controller configured to synchronize the application of heat with movement of the cartridge and / or with the rate of inhalation airflow.

In some embodiments, the device further comprises an electronic unit for controlling (controller) activation of the heating element.

In some embodiments, the device further comprises a communications interface for communicating with one or more external computers and / or systems and / or patient / clinician interfaces.

In some embodiments, the device further comprises or is associated with a dose indicator to provide visual output of vaporization of the pharmaceutically active agent.

In some embodiments, the device is portable and weighs less than about 300 g.

According to some embodiments, the device further comprises or is associated with a storage device adapted to store at least one of purpose data and usage data, the storage device being coupled to a controller adapted to control at least one of the heating element, air flow and a transport mechanism in accordance with the dose and / or data on the treatment regimen.

In some embodiments, the device further comprises a unique identifier adapted to track the use of the device by an associated patient.

In some embodiments, the device further comprises a sensor adapted to detect a physical violation of the device.

In accordance with some embodiments, a method is provided for the controlled vaporization of an active pharmaceutically active agent from a cartridge-shaped plate (dosage unit), said method comprising:

supplying heat to the region of the cartridge to vaporize a predetermined amount of the active pharmaceutical active agent; and moving the cartridge relative to the heat source.

Alternatively, a heating element is contained within the cartridge and the cartridge is moved relative to electrical contacts to power the heating element.

In some embodiments, the method further comprises adjusting at least one of the travel time and speed for vaporization of the active pharmaceutically active agent in accordance with the delivery profile.

In some embodiments, evaporation includes evaporation during pulmonary delivery.

In some embodiments, applying heat includes applying heat to reach a target temperature in less than 500 milliseconds after a trigger signal.

In accordance with some embodiments, there is provided a method for the controlled evaporation of at least one isolated active pharmaceutically active agent from at least one type of plate by applying heat, the method comprising:

heating one or more areas of one or more plates arranged in one or more cartridges with one user switch to release at least one active pharmaceutically active agent. Optionally, the areas contain various isolated active pharmaceutically active agents.

In accordance with some embodiments, there is provided a method of making a cartridge containing a plate containing an isolated active pharmaceutically active agent, the cartridge being adapted for use with a device for automatically applying localized heat to vaporize the pharmaceutically active agent, the method comprising:

applying at least one, optionally, a predetermined amount of the isolated pharmaceutically active agent to and / or onto the plate material;

optionally, measuring the amount of pharmaceutically active agents present in and / or on the loaded plate material, and

pressing the plate into a cartridge.

Optionally, measuring the amount of the pharmaceutically active agent includes one or more of directly measuring the pharmaceutically active agent and weighing the amount of material containing the pharmaceutically active agent.

In some embodiments, compaction of the particle loaded plate material is performed in a cartridge with apertures smaller than the particle size.

In some embodiments, the method further comprises labeling the cartridge with a predetermined amount of the active pharmaceutically active agent.

In accordance with some embodiments, a therapeutic drug delivery cartridge is provided comprising a plate loaded with an isolated active pharmaceutically active agent, said plate being loaded with a predetermined amount of a pharmaceutically active agent per unit surface area of the cartridge, and a heating element.

In some embodiments, the plurality of cartridges are organized as a roll of tape, a carousel (chamomile), or a magazine.

Controlled release and delivery:

In accordance with an aspect of some embodiments, a method is provided for the controlled release of at least one isolated biologically active agent using an inhalation device as described herein.

In accordance with some embodiments, the method is performed using an MDI that is capable of delivering, reproducibly and accurately, by pulmonary inhalation, an amount of at least one vaporizable agent by heating a plate containing the vaporizable agent, in accordance with some embodiments, the vaporization of the agent being effective , and the specified vaporous agent is inhaled by the user. Such MDI requirements are met, for a non-limiting example, by such MDIs as described in International Patent Application No. WO 2012/085919 and in any of US Provisional Patent Applications No. 62/035588, 62/085772 and / or 62/086208, which are fully incorporated into this document by reference, as if they were fully set forth in this document.

Controllability is achieved by one or more of regulating the amount of released biologically active agent (s) in the dosage unit, regulating the heating level supplied to the dosage unit, regulating the current flowing through the heating element and / or its duration, and regulating the configuration and / or flow of air through the air channels in a device that can sometimes provide complete inhalation of the entire volume that includes the vaporous amount of the biologically active agent.

The controllability of a vaporous amount of a biologically active agent in its isolated form provides, for example, methods for using a biologically active agent as a pharmaceutical (drug; medicament) with known and essentially predictable and reproducible pharmacological parameters such as pharmacokinetic (PK), pharmacodynamic ( PD) profile that allows the desired treatment regimen to be achieved to match a known and substantially predictable and reproducible therapeutic window. Thus, in accordance with some embodiments, a method for controlled release by evaporation and pulmonary delivery by inhalation of a predetermined vaporous amount of at least one isolated biologically active agent provided herein is such that the predetermined vaporous amount is selected to exhibit a preselected pharmacokinetic profile and / or a preselected pharmacodynamic profile of the agent in the patient's body.

As used herein, the terms "therapeutic window" and "pharmaceutical window" are interchangeable and refer to the range of pharmacodynamic effects elicited by a range of doses of one or more pharmaceutically active agents, providing a balance between one or more desirable (beneficial) effects and one or more adverse ( negative) effects. In some embodiments, the pharmaceutical / therapeutic window refers to a pharmacodynamic profile. The window can be related to a given point in time, or can span a period of time of any length, including, for example, minutes, hours, days, or longer, shorter, or any intermediate time period. The desirability and undesirability of an effect can be determined based on various criteria and include, without limitation, medical practice, rules and regulations, cultural and demographic norms, genetic factors, and personal preferences and tolerances. For example, the desirability and undesirability of an effect can be determined based on the goal of treatment and based on generally accepted values, and can possibly take into account other parameters such as the patient's preference, ability and activity. It should be noted that this effect can be considered desirable in some cases, but can be considered undesirable in other cases, and vice versa.

It should be noted herein that in some embodiments, by exhibiting a preselected pharmacokinetic and / or pharmacodynamic profile, this means that the vaporous amount of the recovered biologically active agent has been predetermined based on pharmacokinetic / pharmacodynamic (PK / PD) studies conducted in accordance with with well established practice and acceptable standards in at least one subject, by pulmonary delivery to the subject of the agent using an MDI device that is configured to release an accurate and adequate vaporous amount of the agent upon heating the plate containing it, as described herein. It is also noted herein that, in accordance with some embodiments, by exhibiting a preselected pharmacokinetic profile, it means that at least one desired pharmacokinetic profile has been identified, and that at least one predetermined vaporous amount of biologically released the active agent elicits the desired pharmacokinetic profile in the subject. It is also noted herein that in accordance with some embodiments, by exhibiting a preselected pharmacokinetic profile, it means that at least one desired pharmacodynamic profile has been identified and that at least one predetermined vaporous amount of biologically active the agent elicits the desired pharmacodynamic profile in a subject in a reproducible manner. It should also be noted that for some isolated biologically active agents, their ingestion and / or injection by a random subject leads to unpredictable and / or inconsistent and / or non-working values of pharmacokinetic parameters, for which the method provided herein can provide a very advantageous solution.

In some embodiments, the terms "preselected" and "predetermined" refer to or are used interchangeably with the terms "intended," "targeted," "desired," or "desired," or with the terms "effective," "necessary," and "therapeutic." ...

It should also be noted that in this document, the determination of the desired pharmacokinetic profile and / or the desired pharmacodynamic profile is generally performed by performing a PK / PD study for a particular pharmaceutically active agent in a given subject or group thereof. It should also be noted herein that the ability to conduct standard and widely recognized PK / PD assays in a specific subject or group thereof for a pharmaceutically active agent that is delivered by inhalation (pulmonary delivery) with a controlled and reproducible release of a vaporous amount of the isolated biologically active agent by heating containing the plate becomes possible, for example, by means of an MDI device, for example, as disclosed in this document and in international patent application No. WO 2012/085919 and in any of the provisional US patent applications No. 62/035588, 62/085772 and / or 62/086208, all of which are fully incorporated herein by reference.

In some embodiments, the term "predetermined vaporous amount" is also used herein to describe the amount of an agent that is determined based on data indicative of a pharmacokinetic parameter and / or pharmacodynamic parameter, namely, a vaporous amount that was determined by monitoring and / or recording, and / or receiving, and / or analyzing, and / or determining at least one PK parameter and / or PD parameter that is / which are induced by this agent in one or more subjects / patients.

In some embodiments, configuring an MDI device to release a predetermined amount means calibrating the device to develop a preselected PK and / or a preselected PD profile. The controlled, accurate and reproducible release of the isolated biologically active agent from the dosage unit provided herein may allow the MDI device to be calibrated as provided herein.

In accordance with some embodiments, the method is performed by determining at least one pharmacokinetic parameter (also referred to interchangeably herein as a pharmacokinetic effect) and / or at least one pharmacokinetic variable and / or at least one pharmacodynamic parameter (also referred to interchangeably in herein as a pharmacodynamic effect) as these terms are known in the art, which are induced by pulmonary delivery of a vaporous amount of a biologically active agent to a patient using an MDI device:

based on a pharmacokinetic parameter and / or a pharmacokinetic variable and / or a pharmacodynamic parameter, determining a predetermined vaporous amount that exhibits a preselected pharmacokinetic profile and / or a preselected pharmacodynamic profile of an agent in a patient, and

adjusting / re-adjusting / configuring the MDI device to deliver a predetermined vaporous amount of the agent.

Used in this document, the phrase "pharmacokinetic profile" refers to the concentration in the body of a pharmaceutically active agent or its metabolite (for example, an active metabolite), namely, the concentration of an agent or its metabolite in the physiological system of the body (whole body, blood, plasma, lymph, tissue , organ, etc.), into which the connection was introduced as a function of time. Typically, the pharmacokinetic (PK) profile is considered from the time of administration of the compound to the point in time at which the compound is no longer found in the body, or until any time in between; therefore, the PK profile can describe the concentration in the body in a particular physiological system of a particular compound between administration and disappearance under the influence of the mechanisms of release, absorption, distribution, metabolism and excretion / secretion of the compound. Since each organism and each individual organism within the genus of the organism reacts differently to the administration of the agent, the PK profile may be different, and in some cases highly variable from subject to subject, and may differ within an individual subject based on the current physiological state. health status, environmental conditions and even the time of day.

In some embodiments, a pharmacokinetic profile is achieved by providing a subject with one or more of the following:

Dose is one amount of a compound or agent that is administered to him;

Dosing - many predetermined doses that can be different or similar in amount and / or

Treatment regimen is a dosage administered at different time intervals, which may be different or similar in terms of duration. In some embodiments, the treatment regimen also encompasses the delivery period (eg, agent administration period or treatment period).

Alternatively, the treatment regimen is a plurality of a predetermined plurality of predetermined vaporous amounts given at predetermined intervals.

It should be noted that the PK profile can be determined according to the change of the PK parameter depending on the time or the combination of PK parameters depending on the function of time. The PK profile is typically assessed by concentration on a time scale using direct and / or mediated PK measurable effects. For example, the PK profile can be the plasma concentration of a given pharmaceutically active agent in a subject as a function of time.

As used herein, the term "preselected pharmacokinetic profile" refers to a PK profile that has been selected as desired. A pre-selected PK profile may be selected as it has been found to be effective in achieving the desired pharmacodynamic effect in a subject, as described in any of the appropriate embodiments (e.g., to keep the subject within a therapeutic window, as described herein).

PK parameters generally include, without limitation:

C _t , which is the concentration of the agent as determined, measured, or estimated in a particular physiological system (eg, plasma) after administration (delivery, eg, pulmonary delivery) of a dose or treatment regimen to a subject;

C _max , which is the peak concentration of the agent, as determined, measured or estimated in a particular physiological system (usually in plasma), after its administration to a subject;

T _max , which is the time elapsed between the introduction and the achievement of C _max ;

Area under the curve (AUC _{0 → ∞} ; zero to infinity), which is the integral of the concentration versus time curve, usually after a single dose or at steady state;

C _min , which is the lowest concentration of the agent in the body before the next administered dose;

T _min , which is the time elapsed until the detection of C _min or until the next dose is administered;

C _last , which is the last observed quantitative concentration;

λ _z , which is the final constant of the phase velocity;

который представляет собой время, необходимое для того, чтобы концентрация средства достигла половины любого выбранного значения;Half-life

which is the time required for the concentration of the agent to reach half of any selected value;

Elimination rate constant (k _E ), which is the rate at which the agent is removed from the body;

Administration rate (k _m ), which is the rate of administration of the desired elimination balance;

Clearance, which is the volume of plasma cleared from the agent per unit of time;

Bioavailability, which is the systemically available fraction of the agent; as well as

Oscillation, which is the peak of the variation within one dosing interval at steady state.

As a tool for estimating the PK profile in a representative of a population of similar individual subjects (biologically similar, as in a group of people), PK variables that have been found to correlate with the PK profile in a subset of the population can be used to generalize (extrapolate) PK profile for each of the individuals within the entire population. Pharmacokinetic variables typically include, but are not limited to, body weight, height, body mass index (BMI), waist-hip index, lean body mass (LBM), age, race, comorbidities, patient history, concomitant medications, and floor. It should be understood that PK variables depend on the genetic and epigenetic composition of each individual subject and therefore can be used to predict PK / PD profiles in an individual subject with a certain degree of accuracy; however, personalization / individualization of treatment based on the administration of a pharmaceutically active agent is usually based on personal PK / PD parameters (data) defined for an individual subject. In general, the deviation of individual parameters from the average parameters established for the general population is noticeably small.

In the context of some embodiments, the term "treatment" refers to a single pulmonary administration of an agent at a given dose; a fixed and limited series of pulmonary administrations of the agent (dosage) obtained at the same or different doses at the same or different dose intervals (treatment regimens); or chronic treatment that is administered in a limited series, but without the planned discontinuation of treatment (continuous treatment). Typically, a series of predetermined doses administered at predetermined intervals is referred to herein as a treatment regimen or regimen.

In accordance with some embodiments, a dosage unit provided herein is a physical embodiment of a unit dose that is used in a single inhalation session.

In accordance with some embodiments of the method provided herein, pulmonary delivery of the isolated biologically active agent comprises a single dose delivered as one predetermined vaporous amount released by the MDI device in a single inhalation session, or the dose may be administered to a patient in multiple concomitant inhalations. Alternatively, a series of doses, each administered as one or more predetermined vaporous amounts, referred to herein as dosing and administered at predetermined intervals, refers herein to a treatment regimen. The treatment regimen is therefore defined by one or more doses administered in one or more predetermined vaporous amounts (dosing) at predetermined time intervals, each of the predetermined vaporous amounts, doses and dosing intervals being the same or different.

In the context of embodiments, a PK profile of a given pharmaceutically active agent is the result of a dose, dosing and / or treatment regimen with which the agent is administered to a patient, or, alternatively, in accordance with some embodiments, a PK profile is an agent for achieving a specific, preselected or other desired pharmacodynamic profile of the agent in the patient.

As used herein, the term "pharmacodynamic profile" refers to the effect of a pharmaceutically active agent on a subject as a function of time. Accordingly, the term "pharmacodynamic profile" refers to the sum of all biological expressions and body responses, as a function of time, upon administration of a pharmaceutically active agent. A pharmacodynamic profile is typically a direct or indirect result of the pharmacokinetic effect (s) at any given time, or the pharmacokinetic profile of an agent in a patient's body over any given period of time.

The pharmacodynamic profile is the change / variation of directly and / or indirectly determined pharmacodynamic effects as a function of time.

Pharmacodynamic effects can generally be determined, without limitation, by means of a desired (therapeutic) effect (for example, a subjectively perceived therapeutic effect), an undesirable (adverse) effect (for example, a subjectively perceived adverse effect), and also by determining the content of a biomarker (which represents is an indicator of a desired and / or undesirable effect), as these terms are described below. The pharmacodynamic profile, which may be a preselected (desired) pharmacodynamic profile, in accordance with some embodiments, is determined by the therapeutic window of a given agent in a given subject, as defined herein.

The pharmacodynamic (PD) profile is typically a time-dependent assessment and / or measurement on a scale from no response, through the onset of the desired therapeutic effect (below the threshold of the therapeutic effect), through the therapeutic window, through the onset of the adverse effect (above the threshold value of the adverse effect) and up to the toxic effect. A potential advantage of the dosage unit, device, and methods presented herein is the possibility of practical administration by inhalation of certain isolated biologically active agents, which contributes to a more accurate and reproducible assessment of PD parameters in any given subject, compared to the assessment of PD parameters when administered. the same agent by ingestion and / or injection, due to low bioavailability associated with hydrophobicity, viscosity and other agent-specific properties, as discussed above.

The results of such PK / PD studies conducted using the dosage unit, devices and methods provided herein in one or more subjects can therefore be used to determine the initial predetermined vaporous amount of at least one pharmacologically active agent, which immediately upon administration with an MDI device configured for pulmonary delivery would result in an initial preselected pharmacokinetic profile and / or an initial preselected pharmacodynamic profile of the agent in a particular patient, and could subsequently be used to calibrate and preset similar MDI devices in this manner, to deliver an initial predetermined vaporous amount to achieve similar consistent initial results.

It should be noted that in accordance with some embodiments, while a patient / user can initiate pulmonary delivery using an initial predetermined vapor amount that has not been determined based on personal / individual parameters and patient variables, the method provided herein includes an additional step where personal and patient variables are considered in determining a predetermined vapor amount. Thus, in accordance with some embodiments, the method may include personalizing a predetermined vapor amount that results in a preselected PK / PD profile. The personalization step presented below can replace the pre-calibration of the MDI device or act as an additional step after the calibration of the MDI device.

Method of treatment:

Provided herein, a dosage unit used in an MDI device configured to reproducibly and accurately deliver a therapeutic amount of an isolated biologically active agent, or a combination thereof, can be used to treat pathological conditions that are treatable with a biologically active agent, which is preferably administered with by pulmonary delivery (inhalation). Such a method of treatment may be advantageous over other methods, especially when the treatment is carried out using an isolated biologically active agent that is difficult to administer with other modes of administration, or when their administration through other modes is ineffective.

In accordance with an aspect of some embodiments, there is provided a method of treating a patient suffering from a medical condition that is treatable by pulmonary delivery (inhalation) of at least one predetermined vaporous amount of at least one isolated biologically active agent.

The method, in accordance with some embodiments, is performed by pulmonary delivery to a patient of freely respirable vapors of the isolated biologically active agent from a metered dose inhaler device configured to controlled release of at least one predetermined vaporous amount of the agent upon controlled heating of the agent-containing plate.

In some embodiments, the predetermined vaporous amount of the agent is selected to exhibit at least one preselected pharmacokinetic profile and / or at least one preselected pharmacodynamic profile of the agent in the patient.

In some embodiments, the isolated biologically active agent is an isolated cannabinoid such as, without limitation, Δ9-tetrahydrocannabinol (THC), dronabinol ((-) - trans-THC), cannabidiol (CBD), cannabigerols (CBG), cannabichromenes (CBC), cannabinol (CBN), cannabinodiol (CBDL), cannabicyclol (CBL), cannabielsoin (CBE), cannabidivarin (CBDV), tetrahydrocannabivarin (THCV), cannabitriol (CBT), and any combination thereof. Other isolated and volatile biologically active agents are contemplated in the context of some aspects and embodiments of the present disclosure.

In some embodiments, the isolated biologically active agent comprises a cannabinoid and a terpene and / or flavonoid.

Non-limiting representative pathological conditions treated by pulmonary delivery of a volatile, isolated biologically active agent such as cannabinoids, optionally with terpenes and / or optionally flavinoids, include, but are not limited to, alcohol abuse, amyotrophic lateral sclerosis, anorexia nervosa, anxiety disorders, fluctuations appetite, bronchial asthma, atherosclerosis, bipolar disorder, bladder dysfunction, chronic obstructive pulmonary disease (COPD), collagen-induced arthritis, colorectal cancer, Crohn's disease, delirium, digestive diseases, Dravet syndrome, drug addiction and dependence, dystonia , epilepsy, fibromyalgia, generalized epilepsy with febrile seizures plus (GEFS +), glaucoma, glioma, hepatitis C, HIV-associated sensory neuropathic depression, Huntington's disease, high blood pressure, increased intraocular pressure, inflammatory bowel disease (IBD), insomnia, irritable bowel syndrome (IBS), lack of appetite, leukemia, migraine, movement disorders, multiple sclerosis (MS), nausea, neurogenic pain, neuropathic pain, nociceptive pain, Parkinson's disease, phantom pain, post-traumatic stress disorder (PTSD), premenstrual syndrome, pruritus, mental disorders, psychogenic pain (psychogenic or somatoform pain), seizures, septic and cardiogenic shock, sexual dysfunction, skin tumors, sleep apnea, spasticity, spinal cord injury, tics, Tourette symptoms , tremors, unintentional weight loss and vomiting.

In accordance with some embodiments, the method is performed by using an MDI device that is configured to release a predetermined vaporous amount such that the deviation of the actual vaporous amount of the biologically active agent released from the predetermined vaporous amount of the agent is 20% or less, 15% or less , 10% or less, or 5% or less of a predetermined vaporous amount.

In some embodiments, the method is performed such that the deviation of the actual pharmacokinetic profile from the preselected pharmacokinetic profile is 40% or less than the preselected pharmacokinetic profile. Alternatively, the deviation is 35% or less, 30% or less, 25% or less, or 20% or less. It should be noted that the bias may be in the pharmacokinetic profile or in one or more of the profile's constituent pharmacokinetic parameters, for example, C _t or C _max . Such variances are expected to be low even for isolated biologically active agents that have been found to be unfavorable for ingestion and injection, due to the low variability between PK parameters obtained using the dosage unit provided herein in correct, consistent and accurate MDI device.

In some embodiments, the method is performed such that the deviation between the perceived PD profile and the preselected PD profile at any given time is 25% or less, 20% or less, 15% or less, 10% or less, or 5%. or less. The deviation between the sensed PD profile and the preselected PD profile at any given time can be estimated by determining the PD parameter as described above. The variance is expected to be low also due to the low variability between the PK parameters described above.

Since the device can be configured to sequentially deliver any precise amount so as to exhibit any preselected PD profile in a patient, the device and method provided herein can implement a preselected PD profile that can be finely adjusted to be:

within a level lower than the minimum level of therapeutic effect (below the therapeutic window);

within the range from the minimum level of the specified therapeutic effect to the maximum level of the specified therapeutic effect, in which the adverse effect is tolerable and / or acceptable, namely, essentially low or not manifested or not perceived (within the therapeutic window); as well as

within a level higher than the minimum unwanted effect level (above the therapeutic window).

As discussed above, in accordance with some embodiments, the preselected PD profile corresponds to the therapeutic window of the agent in the patient, namely, ranges from a minimum desired effect level to an undesirable effect level.

In some embodiments, the preselected PD profile ranges from a minimum desired effect level to a minimum unwanted effect level.

In some embodiments, the preselected PD profile ranges from the minimum desired effect level to a level higher than the minimum unwanted effect level.

In some embodiments, the preselected PD profile ranges from a minimum level of therapeutic effect to a maximum level of therapeutic effect in which the adverse effect is acceptable.

In any preselected PD profile, the method and device provide high accuracy and reproducibility of results; therefore, in some embodiments, the deviation of the perceived pharmacodynamic profile from the preselected pharmacodynamic profile at any given time is 25% or less, 20% or less, 10% or less, or 5% or less below the preselected PD profile, and / or 25% or less, 20% or less, 10% or less, or 5% or less above the specified preselected PD profile.

A non-limiting example of a pathological condition that can be treated by pulmonary delivery of a vaporizable pharmaceutically active agent is pain that is treatable by pulmonary delivery of dronabinol vaporized from the dosage unit provided herein.

Interface and system:

The dosage unit (cartridge), inhalation device and methods provided herein are highly suitable for personalization, self-dose selection, mechanization and automation of an otherwise complex and cumbersome route of administration and treatment of various pathological conditions that are treatable by inhalation of one or more biologically active funds; While any personalized treatment protocol in accordance with pharmaceutical regulations and requirements presents challenges, reproducible and controlled treatment based on pulmonary delivery of active agents evaporated by heat is a non-trivial task by any measure.

After the problem of accuracy, consistency and reproducibility of the results has been resolved, as has been done, for example, in the MDI device disclosed herein and in WO / 2012/085919, and since the need for calibration and pre-installation of the device has been fulfilled in order to stay within the desired therapeutic window based on widely accepted experimental PK / PD parameters, the inventors of the present invention conceived an integrated system that can control a pulmonary delivery device for isolated biologically active agents using input data collected from various sources in order to provide personalized and effective treatment for any given patient, also in real time.

FIG. 9 is a schematic diagram of a system including an MDI device, physician interface, and / or patient interface, in accordance with some embodiments of the present invention.

In some embodiments, the MDI device 901 is configured to communicate with the physician interface 903 and / or with the patient interface 905. In some embodiments, the MDI device 901 is configured to receive input from one or both of the interfaces 903 and / or 905. Additionally or alternatively , the MDI device 901 is configured to send output data to one or both of the interfaces 903 and / or 907.

In some embodiments, communication between system components is via one or more communication media such as a USB connection, wired connection, wireless connection, and / or any suitable wired and / or wireless communication protocol.

In some embodiments, communication between system components occurs through one or more communication modules, such as communication module 907 of MDI device 901, communication module 909 of doctor interface 903, and / or communication module 911 of patient interface 905.

In some embodiments, the MDI device 901 comprises a controller 913 configured to, for example, activate heating of the plate, thereby vaporizing the active agent, adjust the heating profile and / or activate heating, adjust the cartridge feed mechanism of the MDI device, read data from the device memory 919 MDI 901, energy management and / or other functions. In some embodiments, controller 913 communicates with memory 919. Additionally, memory 919 is configured to store recipe data, personal use data, patient data, patient-received personal PD parameters, dose, dosing, and / or schema modifications. treatment, parameters obtained from the patient in response to a change in dose and / or treatment regimen, and / or other values or information. In some embodiments, controller 913 activates pulmonary delivery of the active agent in accordance with dose, dosing, and / or treatment data stored in memory 919.

In some embodiments, memory 919 is configured to store usage data and / or patient feedback data regarding a particular dose and / or treatment regimen and / or with respect to a preselected (desired) PD profile of the active agent in the patient's body.

In some embodiments, a physician interface 903 comprising, for example, one or more of controller 915, memory 921, and / or communication module 909, is configured for a personal computer (tablet, laptop, desktop, or others), mobile device such as as a smartphone, portable device, wearable device, wrist or goggle device, clinic or hospital monitor, and / or any other suitable device. If necessary, the physician is provided with remote access to the MDI device 901. Additionally or alternatively, the physician directly activates the MDI device 901. In some embodiments, the physician pre-programs (pre-calibrates or sets) the MDI device 901 with a predetermined vapor quantity (dose, dosage and / or an administration regimen) suitable for a particular patient. In some embodiments, data is sent from the physician interface 903 to the patient interface 905, for example, to instruct the patient or to make pre-configured adjustments.

In some embodiments, patient interface 905, comprising, for example, one or more of the following: controller 917, memory 923, and / or communication module 911, configured for a personal computer (tablet, laptop, desktop, or others), mobile device such as a smartphone and / or the MDI 901 itself.

In some embodiments, patient interface 905 accepts input 929. Input may be obtained from one or more of the following: patient, physician interface, database server, MDI device. Examples of different types of input data may include a dose and / or treatment regimen determined by a physician and received through the physician's interface, the current personal PD parameter of the patient entered by the patient and / or received from the patient, personal statistics recorded, for example, on a server databases and / or in the memory of the MDI device, an indication of the duration of inhalation and / or the volume of inhalation read by the MDI device, and / or other types of input.

In some embodiments, patient interface 905 includes a display 927.

Optionally, the display is an interactive display such as a touchscreen of a smartphone, portable device, wearable device, wrist device, or goggle-integrated device.

In some cases, some functions, such as transmitting data to a doctor, accessing a database to obtain information such as user / patient instructions, and / or other functions are activated through the patient interface 905, while other functions such as such as changing a predetermined vapor amount (dose), dosage and / or treatment regimen, viewing other patient protocols, and / or other functions are not permitted through patient interface 905. If necessary, the physician sets patient interface access definitions to an individual patient.

In some embodiments, the patient interface 905 and / or the MDI device 901 is configured to notify the patient whenever pulmonary delivery (inhalation) is required. If necessary, notification is carried out automatically based on the planned dosage (treatment regimen) stored in the memory. Additionally or alternatively, the notification is set by the patient. Additionally or alternatively, the notice is issued by the attending physician.

In some embodiments, one or more system components communicate with the database server 925 by receiving input from the database and / or sending information to the database. In some embodiments, the database contains individual patient data, for example, including the patient's medical history, data transmitted by the MDI device 901, input from a physician, input from a patient, and / or other information. Optionally, the database server is configured to perform computations on the data. In some embodiments, the database server 925 contains collective data including, for example, one or more of the following: clinical experimental results, other patient results, research data, and / or other data. Optionally, the database server 925 communicates with a variety of processing systems used by different patients. Data on various interactions between patients and the MDI device are collected in a central database, continuously examining individual patient usage profiles and recommending dose, dosage and / or treatment regimen, respectively. The use of a shared user database can improve the creation of an accurate predictive dose, dosing and / or treatment regimen for existing and new patients, improving the overall therapeutic success rate of treatment.

According to some embodiments, in accordance with personal feedback received from the patient using the MDI device 901 and / or using the patient interface 905, a predetermined vapor amount (dose, dosing, and / or treatment regimen) is automatically changed by the interface controller 917 and / or MDI device controller 913 to compensate for inadequate settings or misuse of the MDI device, for example, in a situation in which the patient does not use the MDI device when prescribed and / or the use of the MDI device occurs at a different time from the prescribed treatment regimen. In response, one or more actions can be taken, for example, delaying the next dose, increasing or decreasing the next dose (and / or subsequent doses) and / or otherwise changing the treatment regimen.

In some embodiments, a patient using the MDI device 901 may wish to schedule their dose, dosing, and / or treatment regimen so that potential adverse effects are less likely to interfere with the patient's daily activities. While some adverse effects are tolerable at home or at certain times of the day and are an acceptable compromise for symptom relief, these adverse effects may be undesirable when the patient engages in activities such as driving, attending a meeting, and / or other activities. Optionally, using the patient interface 905 and / or by directly activating the MDI device 901, the patient adjusts the dose, dosage, and / or treatment regimen so as to less interfere with his or her intended activity.

Additionally or alternatively, the MDI device 901 and / or patient interface 905 is configured to actively enforce a specific dose and / or treatment regimen, for example, based on input from the patient. For example, a patient enters his planned daily activities and the timing of these activities, and the dose, dosage and / or treatment regimen is automatically adjusted accordingly. Optionally, the dose, dosage and / or treatment regimen is automatically adjusted to ensure that the patient is in a suitable state to perform the intended activity, for example, by ensuring that while driving, the level of adverse effect is relatively low or not perceived.

In some embodiments, the patient can voluntarily change the dose, dosing and / or treatment regimen, for example, using the patient interface 905. If necessary, the degree of modification is limited to prevent a condition in which the patient is in danger, for example, to prevent overdose.

In some embodiments, the patient can simply use the MDI device 901, even if not specifically prescribed. In such a case, the next dose and / or treatment regimen can be automatically modified in response to use. Optionally, the patient is notified of dose and / or schedule modifications via the patient interface 905.

Additionally or alternatively, the physician is notified of such modifications, for example, via the physician interface 903.

FIG. 7 is a flow diagram of a method for administering a treatment regimen to a patient using an MDI device to deliver at least one active agent, in accordance with some embodiments.

In some embodiments, the physician may choose to treat the patient by pulmonary delivery of one or more active agents using an MDI device (1001).

In some embodiments, patient data such as one or more, for example, of the following: PK variables (eg, age, sex, body mass index, etc.), pathophysiological status, pharmacogenetic and / or pharmacogenomic variables, and / or other parameters entered into the system (1003), for example, by a physician and / or other clinical personnel. Optionally, patient parameters and personal variables are entered using the physician interface.

In some embodiments, the intended dose, dosage, and / or treatment regimen is formulated (1005). Optionally, the dose, dosage, and / or treatment regimen is created automatically, for example, using a physician interface software. Additionally or alternatively, the dose, dosage, and / or treatment regimen is planned by the physician. In some embodiments, the dose, dosage, and / or treatment regimen is created by matching the entered patient data with a predetermined dose and / or treatment regimen using data from a database or personalized feedback data, or, for example, in accordance with a reference table.

In some embodiments, the expected PK / PD profile of the patient is simulated (1007) for a selected dose, dosage, and / or treatment regimen. In some embodiments, an expected PK / PD profile is modeled, including, for example, therapeutic effects and / or adverse effects. In some embodiments, a therapeutic window is selected by correlating the pharmacodynamic profile and / or pharmacokinetic profile and the patient's personal data. Optionally, PK / PD profile simulations and / or a preselected therapy window are graphically displayed by the physician, for example, on a physician interface display. When considering the simulation, the physician may decide to change the dose, dosage and / or treatment regimen to more closely match (personalized) the patient (1009). In some cases, the physician may decide to change the parameters, the proposed dose and / or treatment regimen, such as one or more doses, dosage, treatment regimen or total duration of treatment, and / or other treatment parameters.

In some cases, treatment includes the administration of two or more biologically active agents from one, two or more plates, simultaneously or sequentially, to obtain the desired therapeutic effect in the patient. The system, in accordance with some of any of the embodiments, includes the use of an MDI to deliver more than one pharmaceutically active agent (from one or more plates) in any ratio or in any predetermined vaporous amounts to exhibit a preselected PD profile (e.g., maintaining individual patient within the patient-specific therapeutic window). In some embodiments, different doses are selectively administered according to an administration schedule so as to avoid adverse effects while maintaining symptom relief.

In some embodiments, the patient is administered a selected (and possibly improved) dose, dosage, and / or treatment regimen (1011).

In some embodiments, as a test and for a specified period of time during which the patient is treated (e.g., for several hours, during the day, within a week, within a month, and / or for intermediate, longer or more short periods), the physician obtains one or more metrics, such as metrics for overall patient use of the device, metrics for dose, dosing, and / or patient regimen, patient dosage units, one or more of the patient's personal PD parameters, for example, due to the presence of adverse effects, such as psychotropic level, and / or indicators related to the intensity of symptoms, such as the level of pain and / or the content of one or more biomarkers, and / or other indicators (1013). If necessary, one or more indicators are provided in real time. Additionally or alternatively, the indicators are provided at the end of the pulmonary delivery of the device. Additionally or alternatively, the indicators are provided at the request of the physician.

Additionally or alternatively, the patient decides when to send the readings to the physician.

According to some embodiments of the present invention, the metrics are communicated to the physician via the MDI device and / or via the patient interface, automatically and / or in response to instructions from the physician and / or patient. Optionally, one or more metrics are stored in the database for later use.

In some embodiments, based on the metrics provided, the dose, dosage, and / or treatment regimen is adjusted or otherwise modified (1015). If necessary, the modification is performed in real time. In some embodiments, a particular dose, dosage, and / or treatment regimen is modified, as needed, in real time. In some embodiments, the dose and / or treatment regimen is modified based on the upper and lower limits of the PD parameter determined separately for each patient. The upper limit may allow a dose, dosing and / or treatment regimen above which significant adverse effects are present. The lower limit may allow a dose and / or treatment regimen below which the symptom to be treated by delivery of the active agent is not sufficiently mitigated.

FIG. 8A-D are schematic diagrams (FIG. 8A) and screen views (FIGS. 8B-D) of a physician's interface for selecting and prescribing a dose, dosing, and / or treatment regimen for a patient, in accordance with some embodiments.

FIG. 8A shows the general display 1107 of the physician interface. In some embodiments, patient data is entered by a physician through gateway 1109.

In some embodiments, a graphical display of the expected and / or preselected pharmacokinetic profile 1111 and / or the expected and / or preselected pharmacodynamic profile 1113 is presented to the physician. Optionally, one or more of the profiles are shown, individually or together, in relation to time series 1115, including, for example, the duration (eg, hourly scale) during which the patient is being treated. In some embodiments, a therapeutic window 1117 is determined by setting an upper limit 1119 and a lower limit 1121. In some embodiments, the dose, dosage, and / or treatment regimen is selected to obtain expected and / or preselected PK / PD profiles that fit within the range therapeutic window 1117.

In some embodiments, the limit is defined as a constant value represented as a straight line, for example, as shown in FIG. 8A. Alternatively, the limit can contain a changing set of values and be represented as a curved line. For example, the lower limit 1121 represents the desired therapeutic effect, the upper limit 1119 represents the acceptable adverse effect, and a higher threshold C _{max of the} pharmacokinetic profile may be set for the initial portion of the exposure, for example, to accelerate symptom relief, and the threshold C _max may be decreased along as treatment continues as desired. In some embodiments, the dose and / or treatment regimen is selected and / or adjusted to achieve an initial accumulation of active agent in the patient, for example, during the initial part of treatment, and then to provide a constant dosing to maintain the patient in a steady state (maintenance dosing). In general, the initial accumulation of agent is based on a relatively large amount of agent compared to the amounts reported for maintenance dosing.

In some embodiments, for example, when improving a predetermined vapor amount of an agent (dose, dosage, and / or treatment regimen) for an individual patient, the physician may perform one or more of increasing and / or lowering the 1119 limit and / or 1121 limit, increasing and / or lowering the peaks of profile 1113 and / or profile 1111, expanding and / or shortening the duration of treatment along the time axis, and / or other modifications.

It should be noted that the graphical representation is shown herein by way of example and that various graphical representations such as histograms may be used. In some embodiments, the profile 1111 and / or the profile 1113 may be discontinuous, such as a plurality of dots.

FIG. 8B shows a simulation of the expected pharmacokinetic profile of a patient using a predetermined vaporous amount delivered in accordance with a predetermined administration schedule, in accordance with some embodiments. In this example, for the physician interface screen, the physician can fill in patient 1101 data (e.g., gender, weight, height, drug injected, patient ID, and / or other data), and extrapolate the pharmacokinetic profile of an individual patient, as shown, for example , using graph 1103, simulating the concentration of the active agent in the patient's plasma over time.

Similarly, in FIG. 8C shows an extrapolation 1105 of the expected pharmacodynamic profile of an individual patient, showing the level of adverse effect on the patient over time.

FIG. 8D is a screen shot of a doctor's interface in accordance with some embodiments of the present invention. The simulated pharmacokinetic profile is represented by graph 1103 and the simulated pharmacodynamic profile is represented by graph 1105, which are displayed on time series axis 1115, in this example representing an 8 hour period. The patient's pharmacodynamic parameter scale is visually divided into sections indicating, for example, the state of "pain" (below the therapeutic level of effect), indicating the "optimal" state (within the therapeutic window), indicating, for example, the "psychoactive" state (above the level Adverse Effect) as determined in an individual patient, and the simulated PK / PD profiles as graphs are shown in relation to these sections. In this simulation, the first dose is delivered at 8:00, resulting in a change in both pharmacodynamic and pharmacokinetic parameters, moving from the pain section to the optimal section. The second dose, given at 11:00, has been shown to keep the patient within the "optimal" (therapeutic window).

FIG. 9 is a flow diagram of a method for obtaining feedback from a patient and modifying / adjusting a dose and / or treatment regimen accordingly, in accordance with some embodiments.

In some embodiments, a patient's personal PD parameter (1201) is obtained. In some embodiments, the PD parameter refers to an adverse effect such as a psychotropic level, a therapeutic effect such as a pain level, and / or a change in any of these levels. The PD parameter can include an absolute level quantification and / or a relative level quantification, assessed, for example, relative to the level measured before delivery of the dosage unit and / or before delivery of the dosage and / or treatment regimen. The PD parameter can be obtained before, during and / or after delivery of the dosage unit and / or before, during and / or after delivery of the dosage and / or treatment regimen, and / or before, during and / or after the total period of time, during which the patient is provided with treatment.

In some embodiments, the PD parameter is provided directly by the patient, such as through a patient interface. In some embodiments, the patient can manually adjust the visual representation of the PD parameter based on a personal determination of the PD parameter level. As an example, a patient can raise or lower a bar on a graph indicating pain level, for example, on a touch screen of a cell phone and / or any other personal device on which the patient interface is configured.

In some embodiments, patients who are unable to articulate PD parameter levels can use an interactive toolbox to assist them in determining their current PD parameter level, for example, as described below.

Additionally or alternatively, to a conscious, subjectively perceived PD parameter indicated by the patient, a personal PD parameter, such as a biomarker, is obtained through the patient's interface and / or system, for example using a sensor. In some embodiments, one or more standard cellular telephone and / or personal computer components on which the patient interface is configured to act as a sensor to obtain a parameter. Some components that can be used as sensors for obtaining PD parameters from a patient may include: a touch screen that can be used, for example, to assess dexterity, eye-hand coordination and / or memory and mental state; gyroscope, accelerometer, proximity sensor and / or gesture sensor, for example, an IR sensor can be used, for example, to assess motor skills; the camera and / or light source can be used, for example, to detect visual tracking, saccadic dispersion, vasodilation of the eyes, dilation and / or pulsation of the pupils; RGB lighting can be used, for example, to assess the perception of the environment; a magnetometer and / or GPS can be used, for example, to estimate orientation; a speaker and / or microphone can be used, for example, to assess auditory and / or vocal skills; a temperature and / or humidity sensor can be used, for example, to estimate body temperature.

In some embodiments, the MDI device is configured to receive personalized feedback data. By way of example, an MDI device includes a flow sensor and / or a pressure sensor. Optionally, a patient's breath-related metric is obtained using a flow and / or pressure sensor. In some embodiments, the sensor is adapted to detect the volume of inhalation. Because there may be a correlation between inhalation volume and a PD parameter, such as pain level, some embodiments initiate flow and / or pressure measurements to determine the PD parameter in a patient.

Once one or more personal PD parameters are obtained, the dose and / or treatment regimen can be modified accordingly (1203). In some embodiments, the dose and / or regimen is modified, on the one hand, to improve or otherwise alter the patient's condition based on the indication provided, and on the other hand, to achieve a preselected pharmacodynamic profile, such as keeping the patient within a therapeutic window between a lower limit for a therapeutic effect that provides symptom relief; and an upper limit for an adverse effect in which the level of an adverse effect is still tolerable. In some embodiments, the MDI device can be configured such that when it is below the minimum therapeutic effect, the patient input can increase the dose and / or adjust the frequency and / or amount of the treatment regimen. Optionally, the dose and / or treatment regimen is modified to achieve a level above the minimum therapeutic effect.

Additionally or alternatively, the dose and / or treatment regimen is modified as much as the maximum adverse effect level allows.

FIG. 10A-E are images from patient interface screens (Fig.10A, Fig.10C, Fig.10E), as well as graphical representations of the expected pharmacodynamic and pharmacokinetic profiles of the patient before and after receiving the input data of the patient's personal PD parameter (10B and 10D, respectively ), in accordance with some options for implementation.

FIG. 10B is an example for a calculated 3-hour treatment regimen for a specific patient (Patient X, 35 years old and characterized by a BMI of 22). In accordance with an example for a design treatment regimen, to keep patient X within the 3 hour therapeutic window, provided by the PK profile represented by the red curve in FIG. 10B, patient X is required to undergo pulmonary delivery of the active agent using an MDI device in accordance with some embodiments at the following time points and using the following doses: 00 minutes, 1.2 mg; 10 minutes - 1.0 mg; 60 minutes - 0.5 mg. The blue curve is an example for the calculated PD profile at the indicated doses. As you can see, the calculated treatment regimen maintains patient X within the levels, namely, below the level of adverse effect and above the level of therapeutic effect, namely, in the therapeutic window 1303 in the range from 2.5 to 7.5 on the scale presented in the example of the adverse psychoactive effect.

FIG. 10C, during and / or after treatment, patient X indicates a desire to change the adverse effect limit, for example, by increasing the level of the psychoactivity bar 1301 on the patient interface screen. By raising the bar, the patient can indicate that he is willing to increase the acceptable level of adverse psychoactive effect. The therapeutic window, as shown in FIG. 10D, then revised based on patient input - for example, the window narrows to a range of 2.5 to 5 on the psychoactivity scale.

The current administered dose and / or treatment regimen can then be modified accordingly. For example, the predetermined vaporous amount that is scheduled for pulmonary delivery, for example 60 minutes after the initial pulmonary delivery, is reduced from 0.5 mg to 0.3 mg in an attempt to reduce the patient's level of adverse effect (psychoactive effect).

In some embodiments, the dose and / or treatment regimen is automatically modified based on patient input. Additionally or alternatively, patient input and / or simulated profiles are transmitted, automatically and / or at the request of the patient, to the physician, and the physician modifies the treatment regimen.

It should be noted that a patient's sensitivity to a therapeutic and / or adverse effect may change during the day, for example, exhibiting higher pain sensitivity in the evening, decreased cognition in the morning, thus the patient may be less responsive to a therapeutic effect in the evening, or more susceptible to adverse effects in the morning.

In addition or alternatively to the level of adverse effect, the patient can indicate the level of therapeutic effect and / or other conditions, and the dose and / or treatment regimen will be modified accordingly.

FIG. 10E shows a patient interface application including an adjustable slider 1305 that is moved by the patient. In some embodiments, the application presents the patient with an estimate of the current condition, calculated based on one or more of the following: a predetermined dose, dosage and / or treatment regimen, previous input from the patient, for example, including biomarkers and / or others. direct and / or indirect personal PD parameters, treatment and history of effects for a particular patient, use of patient records, patient medical conditions, information from a collective database and / or other information.

During treatment and / or after treatment, the patient can drag the slider to reflect their perceived PD profile. For example, if the patient experiences the full therapeutic effect (eg, the patient no longer has pain), the patient can move the slider to an “optimal” state (eg, to a “psychoactive” state).

Using materials from the patient, the patient interface can automatically modify the next dose and / or treatment regimen. In some embodiments, a pointer to modification 1307 is displayed to the patient, for example, notifying the patient that the next dose is increased. Optionally, the application is configured to request confirmation 1309 from the patient to change the dose, dosage, and / or treatment regimen.

In some embodiments, patient input and / or modified settings are automatically transmitted to the physician's interface. In some cases, the physician may decide to manually change the newly defined dose settings and / or treatment regimens.

FIG. 11 is a flow diagram of a method for measuring one or more biomarkers using a personal handheld device and / or using an MDL device and appropriate dose modification and / or treatment regimen, in accordance with some embodiments.

In some embodiments, one or more biomarkers are measured (1401). In some embodiments, the biomarkers indicate the existence and / or severity of adverse effects in a treated patient. Optionally, biomarker measurements are used to determine the therapeutic window for an individual patient and / or to control the dose and / or treatment regimen to keep the patient within the therapeutic window.

Adverse effects, such as cognitive impairment and other psychoactive effects, may differ among patients with different genetic and biological traits. Thus, in some embodiments, individual biomarkers, such as CNS biomarkers, are obtained from a patient using, for example, one or more sensors in the system, and / or one or more sensors installed in an interface of a patient device, such as sensors in cell phones. for example, as described above.

Some non-invasive biomarker assessment methods may include one or more of the following: saccadic eye movement assessment (e.g. saccadic movement), memory testing, adaptive tracking, digital tapping assessment, body balance assessment, visual analogue scale and / or other methods estimates.

In some embodiments, various art-known non-invasive tests of biomarkers, such as cognitive tasks, including, for example, reaction time, attention, visuo-spatial orientation, title reproduction, narrative reproduction, face reproduction, name associations, may be performed. face, formation, fluency of speech, naming of objects, implicit memory, logical thinking and / or other cognitive tasks.

In some embodiments, the biomarker measurements are reported to the physician (1403). Optionally, the PD parameter measurements are stored in the MDI device memory and / or patient interface memory. Additionally or alternatively, the PD parameter measurements are loaded into a database. Optionally, PD measurements are compared to PD measurements stored in a database, including, for example, previous PD measurements of a particular patient, PD measurements of other patients, PD measurements from the literature, etc.

In some embodiments, the dose and / or treatment regimen is modified in accordance with the PD parameter measurements (1405).

FIG. 12A-C are patient interface screens containing various applications for obtaining PD parameter data and / or for assisting a patient in determining a vaporized amount of an agent (dose and / or treatment regimen), in accordance with some embodiments.

In an example application shown herein that may be installed on a personal portable device such as a cell phone and / or tablet computer, the patient interactively performs one or more tasks that may be included as part of a game or the like. based on a personal PD parameter that can be estimated based on the task. In some embodiments, the level of the adverse effect, such as the psychoactive level of the patient, is automatically outputted by the application. Additionally or alternatively, the application assists the patient in vocalizing their perceived therapeutic and / or adverse effect, which can then be provided as a login.

Tasks provided herein, for example, include finger tracking (FIG. 12A), visual target tracking (FIG. 12B), target alignment (FIG. 12C).

Other applications may include various personal PD measurements using actions and techniques known in the art, such as simulated driving, card sorting, arithmetic skill testing, timing, character copying, hand-eye coordination, reaction time, skills. images and / or lettering; and / or other applications, for example, as described above.

FIG. 13 is a schematic diagram of an inhalation device configured to provide automated controlled pulmonary delivery of one or more active agents, in accordance with some embodiments.

In some embodiments, device 1601 includes a dosage unit nebulizer 1603, such as a plate nebulizer, that contains a pharmaceutically active agent and allows the pharmaceutically active agent to vaporize therefrom. In some embodiments, the nebulizer of the dosage unit contains or communicates with the source of at least one plate from which the active agent originates and a mechanism for processing the dosage unit to obtain a delivered active agent, for example, as described above.

The plate can contain various forms such as, for example, solid mass, solid particles or powder. If necessary, the plate is contained in a cartridge, capsule and / or other containers. In some embodiments, the treatment mechanism includes one or more of, for example, heating (for example, to vaporize), aerosolization, causing a chemical reaction, for example, by mixing with other materials, release of the biologically active agent from the container, for example, by breaking the capsule, pressurizing, mobilizing and / or other treatments. Alternatively, the active agent is already in a ready-to-use form and does not require any processing prior to delivery to the user by heating the plate.

In some embodiments, inhalation device 1601 is an MDI device that includes an input 1605. Optionally, input module 1605 is configured to receive data related to a dose and / or schedule of administration according to which the active agent will be delivered to a patient. Additionally or alternatively, input 1605 is configured to receive one or more readings from a sensor (not shown in FIG. 13) located in device 1601 and / or configured outside of device 1601.

In some embodiments, inhalation device 1601 comprises a controller 1607 configured to initiate and / or modify and / or terminate pulmonary delivery of a pharmaceutically active agent. In some embodiments, the controller 1607 controls the nebulizer of the dosage unit 1603, for example, activating heating of the plate with a heating element, such as a resistance heating element.In some embodiments, the controller 1607 activates the delivery of a predetermined vapor amount of the agent, such as a dose and / or a treatment regimen. received as input. In some embodiments, controller 1607 controls the flow of active agent, for example, by activating one or more valves. In some embodiments, the controller is adapted to release the agent based on the current flow rate.

In some embodiments, inhalation device 1601 includes an outlet 1609.

Optionally, outlet 1609 is configured as a mouthpiece for interaction with a patient. As an alternative to the mouthpiece, the outlet 1609 may be a breathing mask, an infant nipple, and / or other structures suitable for delivering a stream of vapor to a patient.

In some embodiments, the components of the device 1601, such as the unit nebulizer and / or the controller and / or other components, are contained within the housing 1611. Optionally, the housing is shaped and sized for use as a portable device.

In some embodiments, MDI device 1601 includes a flow control mechanism.

Optionally, the vapor flow is controlled using one or more valves. In some embodiments, the flow is selected and / or modified for an individual patient, for example, in terms of delivery time and the ability of the active agent to flow to the patient only upon inhalation of the patient, as indicated, for example, by a sensor embedded in the device. In some embodiments, the device is configured to modify the flow to allow the patient to instinctively determine when to stop inhaling, inhale deeper, and / or otherwise change the rhythm and / or intensity of breathing. As an example, an increased volume flow pulse is delivered by the device to instruct the patient to stop inhalation.

In some embodiments, the stream is selected and / or modified to reduce the amount of active agent that remains trapped within the device's downstream tract and is not delivered to the patient. In some cases, the amount of accumulated active agent is reduced to a known, predetermined amount by controlling the flow.

In some embodiments, flow is controlled by controller 1607. Optionally, flow is controlled in accordance with input 1605, sensor data, and / or other metrics.

A potential benefit of a device comprising a patient-specific flow control mechanism may include improved patient delivery accuracy in terms of timing and / or a predetermined vaporized amount of active agent delivered by the device, improving the performance of the MDI system / device.

FIG. 14A is a schematic diagram of a configuration of an inhalation device 1701, in accordance with some embodiments.

In this configuration, the nebulizer of the dosage unit 1703 includes a dosage unit (cartridge) 1705, a heating element 1707, and a substrate 1709 that moves the dosage unit relative to the heating element 1707, for example, to be in contact with or in close proximity to the heating element.

In some embodiments, the heating element is configured to provide localized heating, such as by conduction, convection, and / or radiation. In some embodiments, the plate is heated sufficiently quickly to a temperature suitable for vaporizing the vaporizable pharmaceutically active agent contained therein. In some embodiments, the plate is configured as a movable element that can be selectively and / or locally activated. Optionally, the plate is organized into compact shapes. Optionally, each form is a predetermined vaporous amount.

In some embodiments, vapors released from the plate are collected within a vaporization chamber 1711 from which they are transported to the patient through an exit tract.

Optionally, a valve 1713 is located along the path to control the flow rate.

In some embodiments, the device 1701 includes a mouthpiece 1715 from which vapors are delivered to the patient in response to inhalation. Alternatively, the mouthpiece 1715 can be attached to other elements, such as a mask and / or nasal cannula, optionally with additional oxygen, for example, to deliver a therapeutic agent to a debilitated patient. Optionally, the mouthpiece is in fluid communication with the 1713 valve.

In some embodiments, the device 1701 includes a power source 1717, such as a battery, a hand-wound spring, and / or a plug.

In some embodiments, device 1701 includes a controller 1719, for example, as described herein above, configured to control one or more of valve 1713, power supply 1717, and / or dispense unit nebulizer 1703 as fully and / or separately controlled dispensing unit atomizer components. In some embodiments, controller 1719 verifies that the dosing unit is allowed to be used.

In some embodiments, the controller 1719 communicates with a memory 1721 that can be read by the controller and / or written to.

FIG. 14B illustrates a dispensing unit 1723 containing a plurality of discrete plates 1725. Each plate 1725 comprises one or more sections or surface areas 1727 for vaporizing one or more isolated biologically active agents contained within a heating element 1729 that functions as a plate body. In some embodiments, the heating element 1729 is in the shape of a cage-like network of wires that wrap the plate. In some embodiments, in order to vaporize the active agent, an electric current is passed through the heating element 1729, heating the loaded plate contained within a particular individual dosage unit. The vapors produced are optionally collected in an evaporation chamber and delivered to the patient.

A potential advantage of individually heated dosage units may include more precise control over predetermined vaporous quantities of biologically active agent delivered to a patient, for example, as compared to a moving belt of dosage units heated by a stationary heating element. Individual loading and heating of a specific dispensing unit at a specific point in time can improve the accuracy of the MDI device.

FIG. 15 is a flow diagram of a method for treating an individual patient using the system of FIG. 6 while keeping the patient within the therapeutic window, in accordance with some embodiments.

In some embodiments, the MDI device is programmed for a predetermined vapor amount (doses and / or treatment regimens) (1801). Optionally, the dose and / or treatment regimen is set in the inhalation device by a physician, manually (eg, by activating buttons on the device itself) and / or using a physician interface. Additionally or alternatively, the dose and / or treatment regimen is set in the MDI device in accordance with instructions sent from the patient interface.

In some embodiments, the device is activated to deliver an active agent to a patient (1803). In some embodiments, direct and / or indirect feedback from the patient is obtained in real time (1805). Optionally, the feedback data is obtained during pulmonary delivery (inhalation session). Treatment can typically begin with pulmonary delivery and end 5-20 minutes thereafter, for example when the preselected pharmacodynamic profile is fully developed for the active agent and / or at a later time. Additionally or alternatively, feedback data is obtained during a series of pulmonary deliveries, for example, over a period of time of 1 hour, 3 hours, 5 hours, 9 hours, 12 hours, or intermediate, longer or shorter periods of time. The protocol may include 5-10 pulmonary deliveries per day, at timed intervals ranging from 15 to 180 minutes between successive pulmonary deliveries.

In some embodiments, the feedback data obtained from the patient includes personal PD parameters such as therapeutic effects, eg, intensity of symptoms, and / or adverse effects, eg, psychoactive state of the patient.

In some embodiments, the patient interface interacts with the patient to obtain feedback data. In some embodiments, questions for the patient regarding their current state are displayed on a screen and the patient answers the questions. Such a question can be presented, for example, in the form of a bar indicating the level of pain, for example, which the patient raises and / or lowers. Additionally or alternatively, the feedback data is obtained using one or more applications, such as games, with which the patient interacts. Optionally, the content of non-invasive biomarkers is assessed by analyzing the patient input when interacting with the user interface. Additionally or alternatively, patient feedback data is obtained by measuring various biomarkers using one or more sensors, for example by using components of a smartphone, handheld device, wearable device, wrist device, or goggle-integrated device to act as non-invasive sensors. biomarkers.

In some embodiments, the personal PD parameters are obtained periodically, for example, semi-daily, daily, weekly, monthly, as required, for example, before a dose and / or series of doses, before and / or after a change in dosage and / or administration schedule, or otherwise.

In some embodiments, the parameters, dose, and / or treatment regimen are modified in response to PD (1809). Optionally, the dose and / or treatment regimen is modified to achieve the desired effect, for example, to reduce the patient's pain level while keeping the patient within the therapeutic window. In some embodiments, the dose and / or treatment regimen is iteratively modified through the patient interface. The modifications can occur multiple times, for example, during, between or after one or more pulmonary deliveries and / or during the total time of the treatment period (days, weeks, months, years) to which the patient is subjected. The modification is limited by safety cutoffs, such as doses that could put the patient at risk.

In some embodiments, the patient interface and / or inhalation device (MDI) reminds the patient to perform one or more pulmonary deliveries (1811). Such a reminder can be provided in the form of a visual signal (eg, light indication), sound, vibration, notification on a portable / handheld device such as a smartphone, handheld device, wearable device, wrist device, or a device built into goggles, or a combination thereof.

In some embodiments, patient usage data is recorded and stored in the MDI device memory and / or in the patient interface memory. If necessary, the delivery of the active agent is modified, potentially in real time, according to the usage data. For example, in the event that a patient has missed one or more pulmonary deliveries, the dose and / or treatment regimen can be automatically modified to accommodate delivery of, for example, an increased amount of active agent to the next one or more pulmonary deliveries.

In some embodiments, one or more of the acts described in 1801-1811 may be repeated. Preferably, obtaining personal PD parameters and / or usage data from a patient repeatedly may involve continually adjusting the dose and / or treatment regimen, providing flexible, correct and accurate individual patient treatment based on the actual treatment effect on the individual patient.

It is expected that during the patent life resulting from this application, many appropriate dosage units will be developed for evaporation and delivery by inhalation of isolated biologically active agents, and the scope of the dosage unit term is intended to include all such new technologies a priori.

The dimensions and values disclosed herein are not to be understood as being strictly limited to the exact numerical values. Instead, unless otherwise specified, each such dimension shall denote both the specified value and a functional equivalent interval surrounding that value. For example, the disclosed size "10 microns" is intended to mean "about 10 microns".

As used herein, numerical ranges preceded by the term "approximately" should not be construed as being limited to the specified range. Rather, the numerical ranges preceded by the term "about" are to be understood as including the range accepted by those of ordinary skill in the art for any given element in the microcapsules or formulations of the present invention.

As used herein, the term "about" means being within an acceptable error range for a particular value, as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, that is, the limitations of the measurement system. For example, "about" can mean a range of up to 10%, more preferably up to 5%, and even more preferably up to 1% of a given value. Where specific values are described in the application and in the claims, unless otherwise indicated, the meaning of the term "approximately" is within the acceptable range of errors for a particular value.

The terms “comprises”, “comprising”, “includes”, “including”, “having” and related words mean “including without limitation”.

The term "consisting of" means "including and limited to".

The term "consisting essentially of" means that the composition, method or structure may include additional ingredients, steps and / or parts, but only if the additional ingredients, steps and / or parts thereof do not significantly affect the main and new characteristics of the claimed composition, method or structure.

Used in this document, the singular includes references to the plural, unless the context clearly dictates otherwise. For example, the term "compound" or "at least one compound" can include a variety of compounds, including mixtures thereof.

The words "example" and "illustrative" are used herein to mean "serving as an example, instance, or illustration." Any embodiment described as "example" or "illustrative" should not necessarily be construed as preferred or advantageous over other embodiments and / or exclude the inclusion of elements from other embodiments.

The word "optional" is used herein to mean "provided according to some embodiments and not provided according to other embodiments". Any particular embodiment may include many "optional" features, unless such features conflict.

In the present application, various embodiments may be presented in a range format. It should be understood that the description in the format range is presented simply for convenience and brevity and should not be construed as an inflexible limitation on the scope of the invention. Accordingly, the description of the range should be considered to specifically disclose all possible sub-ranges, as well as individual numerical values within this range. For example, a description of a range such as 1 to 6 should be considered as a range specifically disclosing all possible sub-ranges such as 1 to 3, 1 to 4, 1 to 5, 2 to 4, 2 to 6, 3 to 6, etc., as well as individual values within this range, such as 1, 2, 3, 4, 5, and 6. This applies regardless of the width of the range.

Whenever a range of numeric values is specified herein, it is intended to include any cited numeric value (fractional or integer) within the specified range. The phrases "varying in the range / varies in the range between" the first indicating number and the second indicating number and "varying in the range / varies in the range from" the first indicating number "to" the second indicating number are used interchangeably herein and are intended to include the first and second indicating numbers and all fractions and integers in between.

As used herein, the term "method" refers to approaches, tools, technologies and procedures for performing a given task, including, without limitation, approaches, tools, technologies and procedures either known or readily developed from known approaches, tools, technologies and procedures by chemical practitioners. , pharmacological, biological, biochemical and medical technician fields.

As used herein, the term "treatment" includes abolishing, substantially inhibiting, slowing or reversing the progression of a condition, substantially alleviating the clinical or aesthetic symptoms of the condition, or substantially preventing the onset of the clinical or aesthetic symptoms of the condition.

All measured values are assumed to be measured under standard conditions of temperature and pressure, or the like, unless otherwise indicated.

It should be understood that certain features of the invention, which for clarity are described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which for brevity are described in the context of one embodiment, may also be presented separately or in any suitable subcombination or as suitable in any other described embodiment. Certain functions described in the context of various embodiments should not be construed as essential features of these embodiments unless the embodiment is idle without these elements.

Various embodiments and aspects of the present invention, which are outlined above and claimed in the claims, find experimental confirmation in the following examples.

EXAMPLES

The following examples, together with the above descriptions, illustrate some embodiments of the present invention in a non-limiting manner.

Example 1

A piece of sintered glass with a porosity of 30 (laboratory standard), having the dimensions of a plate suitable for installation in the frame or body of the plate, was used as a single breathable matrix.

A solution was prepared from 50 mg of isolated and purified CBD in 50 microliters of ethanol. The solution was poured onto an air-permeable matrix such that the solution remained entrapped and impregnated in the matrix without leaching.

Loaded breathable matrix, i.e. the plate was placed in a drier to evaporate ethanol at a temperature below the boiling point of the CBD, such as 100 ° C.

After the ethanol was evaporated, which was judged upon reaching a constant plate weight, the plate was ready to continue mounting the dosage unit. After the plate was positioned in the metering unit frame, the mesh was fused to the metering unit frame using a heat press (by melting the frame and overlapping mesh), ultrasonic welding, or, if necessary, any biocompatible adhesive.

CBD has a boiling point of 180 ° C. The time for vaporization and inhalation of the drug is short (approximately only 3 seconds) so that most, if not all, of the drug can be vaporized and inhaled in a single inhalation by most intended users. The plate is quickly heated to a temperature above 180 ° C, but below the combustion temperature of the breathable matrix material, frame material and CBD.

Example 2

A piece of ceramic with a porosity of 30 (laboratory standard), having a plate size suitable for installation in a frame or plate body, was used as a single breathable matrix.

Prepare a solution of 20 mg of pure dronabinol in 50 microliters of ethanol.

The solution is poured onto an air-permeable matrix such that the solution remains entrapped and impregnated in the matrix without leaching.

Loaded breathable matrix, i.e. the plate is placed in a drier to evaporate ethanol at a temperature below the boiling point of dronabinol, such as 100 ° C.

After the ethanol has evaporated, which is judged to have reached a constant plate mass, the plate is ready to continue mounting the metering unit. After the plate is placed in the metering unit frame, the mesh is fused to the metering unit frame using a heat press (by melting the frame and overlapping mesh), ultrasonic welding, or, if necessary, any biocompatible adhesive.

Dronabinol has a boiling point of 250 ° C. A short time is provided for evaporation and inhalation of the drug (approximately only 3 seconds). The plate is quickly heated to a temperature above 250 ° C, but below the combustion temperature of the breathable matrix material, the frame material and dronabinol.

Example 3

A measured amount (eg 30 m ³ ) of acid washed / silanized glass beads having an average size of 75 µm (such as eg SUPELCO 59201) is placed in a dose frame. Optionally, the granules are dispensed in the dose frame by placing them in a horizontal plane with respect to the supporting surface and shaking the dose frame with the granules inside vertically (for example, by vibration of itself and / or the surface on which it is located), until then until an aligned plane of granules is formed in the frame. If necessary, the dose frame is attached before vibration to prevent the pellets from rolling out of the frame from the bottom.

Prepare a solution of 5 mg Δ9-tetrahydrocannabinol (Dronabinol THC-10015S) and 1 mg limonene (Sigma-Aldrich 62118-1 ml) in 50 μl ethanol.

The solution is carefully poured onto glass beads and the dose is placed in a drier to evaporate the ethanol. If necessary, the granules are instead dipped in the solution and then removed to dry before being framed as described above.

After the ethanol is evaporated, which can be estimated, for example, by reaching a constant mass of the pellets or plate (if already formed), the amount of THC and limonene can be measured or estimated, for example, by comparing the weights of the dried coated pellets with the washed pellets before exposure. THS-limonene solution.

Although the present invention has been described in connection with specific embodiments, it will be understood that many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, it is intended to cover all such alternatives, modifications and variations that fall within the spirit and broad scope of the appended claims.

All publications, patents, and patent applications mentioned herein are incorporated by reference in their entirety into the description, to the same extent as if it were specifically and separately indicated that each individual publication, patent or patent application is incorporated herein by reference. In addition, the citation or identification of any reference in this application should not be construed as an admission that such reference is available as prior art to the present invention. To the extent that section headings are used, they should not be construed as a mandatory limitation.

Claims (26)

1. A metering unit for use with an inhaler, said metering unit comprising at least one biologically active agent released by vaporization, said metering unit comprising: a plate containing a solid carrier material, and at least one biologically active agent is in the carrier material and / or on it; breathable electrically resistive heating element in thermal contact with the specified plate; said carrier material has a sufficiently low electrical conductivity to avoid passing current through it instead of said electrically resistive heating element; wherein said carrier material is stable and inert at the evaporation temperature of said at least one biologically active agent. 2. A dispensing element according to claim 1, wherein said carrier material has an electrical resistivity of at least 10 μΩ⋅hm. 3. A dispensing element according to claim 1 or 2, wherein said carrier material has a sufficiently high thermal conductivity to allow the carrier material to distribute heat over said plate. 4. A dispensing element according to claim 3, wherein said thermal conductivity is at least 0.1 W / (m⋅K). 5. The dosage element according to any one of paragraphs. 1-4, in which the specified plate is breathable. 6. A dispensing element according to claim 5, wherein said plate is sufficiently breathable to provide a flow of at least 0.5 liters of gas per minute at a vacuum of at least 1-5 kPa through said plate. 7. Element dispensing according to any one of paragraphs. 1-6, wherein said electrically resistive heating element is in direct contact with at least one surface of said plate. 8. The dosage element according to any one of paragraphs. 1-7, wherein said electrically resistive heating element comprises a resistive grid. 9. The dispensing element according to any one of paragraphs. 1-8, wherein said electrically resistive heating element extends across at least two opposite surfaces of said plate. 10. A dispensing element according to claim 9, wherein said electrically resistive heating element comprises a U-shape with two ends and an opening in which said plate is located such that an electric current flows through both of at least two opposite surfaces, when a voltage is applied between the two ends. 11. A dispensing element according to claim 9, wherein said electrically resistive heating element is secured to said plate, retaining said plate on the dispensing element. 12. Element dispensing according to any one of paragraphs. 1-11, in which said carrier material has a combustion and decomposition and melting temperature higher than the evaporation temperature of the biologically active agent. 13. The dispensing element according to any one of paragraphs. 1-12, wherein said carrier material does not react with the biologically active agent when in contact with the biologically active agent in a temperature range that ranges from storage temperature to the temperature of combustion and decomposition of the biologically active agent. 14. The dispensing element according to any one of paragraphs. 1-13, in which said carrier material does not react with the biologically active agent when in contact with the biologically active agent in a temperature range from storage temperature to a temperature that is 50 ° C higher than the evaporation temperature of the biologically active agent. 15. The dispensing element according to any one of paragraphs. 1-14, in which the specified plate contains packed particles. 16. A dispensing unit according to claim 15, wherein said particles have a diameter greater than 10 microns. 17. The dispensing element according to any one of paragraphs. 1-16, in which the thickness of the specified metering element is a point value in the range from 0.1 to 2 mm. 18. Element dispensing according to any one of paragraphs. 1-17, in which the weight of the specified plate is a point weight value from 1 to 100 mg. 19. The dispensing element according to any one of paragraphs. 1-18, in which the specified plate is formed by pressing the particles into a mold to combine the particles into an air-permeable matrix. 20. The dispensing element according to any one of paragraphs. 1-19, wherein said carrier material is formed from one or more materials including: glass, quartz, ceramic composite, silicon carbide, mullite, alumina, silicone, and polytetrafluoroethylene. 21. The dispensing element according to any one of paragraphs. 1-20, wherein said at least one biologically active agent includes a biologically active agent selected from the group consisting of Δ9-tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerols (CBG), cannabichromenes (CBC), cannabinol (CBN), cannabinodiol (CBDL), cannabicyclol (CBL), cannabielsoin (CBE), cannabidivarin (CBDV), tetrahydrocannabivarin (THCV), cannabitriol (CBT), terpene, flavonoid, and combinations thereof. 22. The dosage element according to any one of paragraphs. 1-21, in which the biologically active agent is provided in and / or on the carrier material in a predetermined amount. 23. The dosage element according to any one of paragraphs. 1-22, wherein said electrically resistive heating element comprises an electrode contact receiving region on either side of a region passing through the plate.

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