Methods, apparatus, and systems for the delivery of active drugs to the lungs

Abstract

To provide a method of pulmonary delivering to a subject at least one pharmacologically active agent being in a plant material.SOLUTION: There is provided a system including a metered dose inhaler device which executes vaporization by vaporizing a pre-determined vaporized amount of the agent by controllably heating the plant material and performs pulmonary delivering at least one pre-determined vaporized amount of at least one pharmacologically active agent in the plant material to the subject. The system further includes a controller that communicates to an inhaler device which is configured to control the pre-determined vaporized amount on the basis of data indicating at least one pharmacodynamic effect induced by the agent in the subject.SELECTED DRAWING: Figure 9

Description

[Technical Field]

[0001] The present invention relates to pharmacology in some embodiments, and more particularly to methods, apparatus and systems for controlled pulmonary delivery of active drugs, but is not limited thereto. [Background technology]

[0002] Natural substances, such as plant-based materials, offer numerous pharmaceutically active agents capable of providing a wide range of therapeutic and other beneficial effects; however, the use of many such substances for direct pharmacological purposes has been limited by technical and cultural reasons. This is primarily because the quantitative determination of the active agents they contain is difficult, and therefore controllable administration is challenging, leading physicians and pharmacologists who recognize the beneficial effects of these substances to be reluctant to prescribe natural substances.

[0003] Cannabis is one of the most used and studied natural substances, and it has been shown to have beneficial effects in treating nausea and vomiting, multiple sclerosis and other neurological conditions, loss of appetite and weight in cancer and AIDS, neurological pain, insomnia, anxiety and depression, epilepsy and other seizures, asthma, opioid withdrawal, and inhibition of primary tumor growth. It has also been shown to be effective for antipyretic and anti-inflammatory uses, anthelmintic uses, anti-migraine and labor-inducing uses.

[0004] Nevertheless, cannabis as a "mainstream" medicine has been a subject of controversy for many years due to the difficulties in administering it according to the typical medical model of drug prescription.

[0005] The inability to administer cannabis accurately and precisely is one of the major obstacles to its inclusion in drug regimens, such as those used for pain management, where it plays a key role. Furthermore, the lack of methods for administering cannabis in pharmaceutical form makes physician prescription and treatment monitoring difficult, and blurs the lines between medical and recreational use. Consequently, regulatory authorities in many countries are reluctant to approve cannabis for medical use. In fact, to date, cannabis has not been recognized by the public as a safe substance and is treated primarily as an illegal substance in most countries around the world.

[0006] For natural substances such as cannabis to be used as "mainstream" medicines, these natural substances must be made available in a way that allows the use of their active ingredients to comply with customary medicinal standards and practices regarding administration and regimens.

[0007] Problems associated with the use of cannabis as a natural substance can be illustrated by a recent study on patterns and prevalence of medicinal uses of cannabis involving 953 participants from 31 countries. This study showed that pulmonary delivery of cannabis was the most preferred route of administration, used by 86.6% of participants (62.9% for smoking and 23.7% for vaporization). Oral delivery of cannabis for edible purposes was used by 10.3% of participants, while only 2.3% used cannabis extract delivered via the oral mucosal route (Sativex®) in tablet form or by synthetic cannabinoids (Marinol® and Nabilone®). This is partly due to the slow and irregular absorption of cannabinoids via oral administration, leading to delayed onset and often insufficient analgesia. Randomized, controlled, double-blind, double-dummy studies on oral mucosal delivery of cannabis revealed similar pharmacokinetic patterns to those of oral use.

[0008] Smoking cannabis products provides a basis for a rapid and efficient method of cannabinoid delivery. During smoking cannabis products, THC plasma levels rise rapidly, typically reaching peak concentrations within 1-3 minutes, resulting in the first onset of effects around 7 minutes later. However, variations in inhalation intensity, smoking duration, and respiratory holding time, as well as the estimated destruction of approximately 30% of the THC dose by pyrolysis during smoking, lead to a heterogeneous bioavailability of 2-56% via the smoking pathway. In addition to this diverse bioavailability, smoking is an undesirable method of cannabinoid delivery due to smoking-related pyrolysis byproducts that can cause various diseases.

[0009] A step forward is being taken by developing cannabis vaporization technology aimed at delivering inhaled cannabinoids while avoiding the respiratory hazards of smoking. While the core temperature of a burning cigarette is 750-800°C, cannabis can be vaporized at 170-190°C. In this temperature range, active cannabinoids, as well as flavonoids and terpenoid vapors, are formed below the combustion point (230-235°C), where pyrolytically decomposable toxic compounds are produced. Vaporization technology has been shown to reduce the formation of carbon monoxide and highly carcinogenic compounds such as polynuclear aromatic hydrocarbons (PAHs), benzene, and tar.

[0010] A recent clinical trial enrolling a patient population with chronic neuropathic pain of various etiologies showed that low doses of Δ 9 - THC has been shown to have a favorable risk-benefit ratio. Ware et al. [Non-Patent Literature 1] showed that compared to placebo, Δ was 9.4% 9 - THC (Total available Δ 9 - A single puff of 25±1 mg of cannabis, including an estimated dose of 2.35 mg based on THC, three times a day for 5 days, is associated with an average C15% blood sugar level. max The concentration was reduced to 45 ng / ml, and the average daily pain intensity was reported to decrease by 11.4%. In another clinical trial, Wilsey et al. [Non-Patent Literature 2] reported that 10.3 mg of vaporized total available Δ 9- It has been reported that when THC was inhaled in two divided doses at 2-hour intervals, pain intensity decreased by 31% and 25% at 3 and 5 hours, respectively. Increasing the THC dose to 28.2 mg produced an isoanalgesic response, which remained stable at these time points. In a second clinical trial, Wilsey et al. [Non-Patent Literature 3] reported that either 19 mg (moderate dose) or 34 mg (high dose) of available total Δ 9 - It has been reported that by having subjects smoke THC in three divided doses, the same level of analgesia was produced at each cumulative dose level, reaching a plateau or "ceiling effect" with a 45% reduction in neuropathic pain.

[0011] However, none of the currently known smokeless vaporizers are suitable for administering cannabis according to general pharmaceutical standards and practices. Lung delivery of cannabinoids in the vapor phase varies within and between doses due to subjective estimation of the user's loaded dose, repeated inhalations at different times with the same loaded dose, inconsistent inhalation kinetics, and time-dependent concentration of vapor within the device. Consequently, vaporizers used today make proper pharmaceutical administration and medical regime monitoring impractical or unfeasible.

[0012] In addition to the ability to control the vaporization rate of pharmaceutically active agents derived from natural plant materials in terms of accuracy and consistency, the problems of administration and regimens related to current methods for delivering such agents to the lungs are usually resolved through trial and error based on the user's subjective perception, since measuring pharmacokinetic and pharmacodynamic parameters is beyond the capabilities of most users.

[0013] Patent Document 1 by the assignees discloses an inhalation device for controlling the extraction / vaporization of plant-derived active agents by heating, in which the plant material is constructed as a cartridge, and the device is configured to vaporize a precise amount of the agent in a highly reproducible manner. The inhaler contains pre-loaded and metered portions of plant material, each associated with a dedicated heating element designed to heat the plant material and thereby vaporize one or more active substances from the plant material. Figure 1 of the background art is a photograph showing an example of such a device.

[0014] Further background information includes Patent Document 2, which discloses an apparatus and method for taking in a substance in an airflow; Patent Document 3, which discloses a vaporizer for vaporizing a substance; and Patent Documents 4, 5, 6, 7, 8, 9, and 10. [Prior art documents] [Patent Documents]

[0015] [Patent Document 1] International Publication No. 2012 / 085919 [Patent Document 2] U.S. Patent Application Publication No. 2005 / 0268911 [Patent Document 3] U.S. Patent Application Publication No. 2011 / 0192399 [Patent Document 4] U.S. Patent Application Publication No. 2005 / 0087189 [Patent Document 5] U.S. Patent Application Publication No. 2007 / 0240712 [Patent Document 6] U.S. Patent No. 6,622,723 [Patent Document 7] U.S. Patent No. 6,830,046 [Patent Document 8] U.S. Patent No. 8,204,729 [Patent Document 9] U.S. Patent No. 8,333,197 [License 10] U.S. Patent No. 8,474,453 [License 11] U.S. Patent Application No. 13 / 997,302 [License 12] International Publication No. 2009 / 063463 [License 13] International Publication No. 2010 / 134068 [Non-licensed literature]

[0016] [Non-licensed Document 1] Ware et al. [in Canadian Medical Association CMAJ. 2010; 182(14):E694-701] [Non-licensed Document 2] Wilsey et al. [in J Pain. 2013; 14(2):136-48] [Non-licensed Document 3] Wilsey et al. [in J Pain. 2008; 9(6):506-21] [Non-licensed Document 4] Zuurman, L. et al. [British Journal of Clinical Pharmacology, 2009, 67(1), pp. 5-21] [Non-licensed Document 5] Ashraf, AB et al., Image and Vision Computing, 2009, 27 (12), p. 1788-1796 [Non-licensed Document 6] Hu, Y. et al., Conference: IEEE International Conference on Automatic Face and Gesture Recognition - FGR, 2008, p. 1-6 [Non-licensed Document 7] Yamaguchi, T. et al., Oral Surg Oral Med Oral Pathol Oral Radiol Endod., 2007 104(5), p. e22-7 [Non-licensed document 8] Rowland M, Tozer TN. “Clinical Pharmacokinetics: Concepts and Applications”. 3th ed., Williams and Wilkins, Media, PA, 1995

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Non-licensed Document 11

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Non-licensed Document 16

[0017] According to one aspect of several embodiments of the present disclosure, a method is provided for delivering at least one pharmacologically active agent present in a plant material to a subject through the lungs, the method comprising the step of delivering the agent to the subject through the lungs using a metered-dose inhalation device configured to vaporize at least one predetermined vaporized amount of agent when the plant material is controlledly heated, the method comprising selecting at least one predetermined vaporized amount of agent to achieve at least one predetermined pharmacokinetic (PK) effect and / or at least one predetermined pharmacodynamic (PD) effect induced by the agent in the subject.

[0018] According to some embodiments, a predetermined vaporization amount is determined based on at least one PK effect and / or at least one PD effect relating to the population.

[0019] According to some embodiments, the method further includes a step of adjusting a predetermined vaporization rate to achieve a predetermined PK effect and / or predetermined PD effect based on data showing that the drug induces at least one PK effect and / or at least one PD effect in a subject.

[0020] According to some embodiments, the method further includes the step of generating data by monitoring at least one PK effect and / or at least one PD effect induced by the drug in a subject.

[0021] According to some embodiments, the method includes the step of delivering to the lungs in at least two predetermined vaporization amounts according to a predetermined regimen.

[0022] According to some embodiments, the method includes a step of adjusting the regimen to achieve a predetermined PK effect and / or predetermined PD effect based on at least one PK effect and / or at least one PD effect induced by the drug in a subject.

[0023] According to some embodiments, the method further includes the step of generating data by monitoring at least one PK effect and / or at least one PD effect induced by the drug in a subject.

[0024] According to some embodiments, monitoring of PK effects and / or PD effects includes receiving data indicating at least one type of PD effect in a subject from at least one sensor communicating with a controller that is in contact with an inhalation device.

[0025] According to some embodiments, the adjustment of a predetermined vaporization amount and / or regimen is based on data received via a user interface device.

[0026] According to some embodiments, the adjustment of a predetermined vaporization rate and / or regime is performed in real time.

[0027] According to some embodiments, monitoring of the PK effect and / or PD effect induced by the drug in the subject is performed at predetermined time intervals before, during, and / or after lung delivery.

[0028] According to some embodiments, the PK effect includes the concentration of a drug in a given volume of body fluid and the concentration of a drug in a given mass of body tissue.

[0029] According to some embodiments, PD effects include desirable effects, undesirable effects, therapeutic effects, adverse effects, and biomarker levels.

[0030] According to some embodiments, the method includes a step of adjusting at least one of a predetermined PK effect and / or a predetermined PD effect based on data received via a user interface device.

[0031] According to some embodiments, a given PD effect is associated with a given PD profile that lies within a range between the minimum level of a desirable effect and the level of an undesirable effect.

[0032] According to some embodiments of the present invention, a given PD profile is in a range between the minimum level of desirable effect and the minimum level of undesirable effect.

[0033] According to some embodiments, a given PD profile lies in a range between a minimum level of desirable effect and a minimum level of undesirable effect.

[0034] According to some embodiments, the step of determining at least one of the desired and / or undesirable effects includes the step of receiving instructions from the subject.

[0035] According to some embodiments, biomarkers include invasively detectable biomarkers and non-invasively detectable biomarkers.

[0036] According to some embodiments, non-invasively detectable biomarkers include heart rate, oxygenation level (SpO2), blood pressure, respiratory rate, body temperature, inhalation volume, facial expression, muscle contraction, convulsions, spasms, sweating, hand-visual coordination, ocular vasodilation, conjunctival and / or scleral redness, intraocular pressure fluctuations, motor function, ataxia, sinus tachycardia, tremor, cardiac arrhythmia, skin conductance / impedance levels, seizures, electromyography (EMG), electrocardiogram (ECG), photoplethysmography (PPG), galvanic skin response (GSR), blue-brown visual inhibition, H-mask visual inhibition, auditory latent inhibition, and visual latent inhibition. Stroop color word, simple response (conflict task), cognitive set switching, logical reasoning, decision time, rapid information processing, perceptual maze, simulated driving, visual search, time estimation, time perception, visual search, attentional search, symbol copying, letter cancellation, alphabet deletion, D2 cancellation, Brickenkamp D2, digit copying test (DDCT), symbol-digit substitution test (SDST), digit-symbol substitution test (DSST), digit vigilance, vigilance, auditory vigilance test, Wesnes / Warburton vigilance task, rapid information processing, CRT + tracking segmented attention, selective attention, cluster Intermediate attention tasks, emotional attention tasks, auditory flutter fusion, flash fusion, critical flicker fusion (CFF), attention continuity, paired associative learning, word list learning, 15-word test, introduction adjustment, delayed word recall, delayed word recognition, delayed picture recognition, word presentation, word recognition, numerical working memory, numerical memory, memory scanning, auditory Brown / Peterson test, visual Brown / Peterson test, visuospatial memory, fragment picture test, Pauli test, block span, number span, number span (forward), number span (backward), WAIS vocabulary, WAIS similarity, word fluency Sexuality, verbal fluency, performance time (delayed word recognition), performance time (numerical working memory), performance time (digital alertness), performance time (rapid information processing), performance time (delayed picture recognition), performance time (visual information processing), simple reaction time CRT, composite RT visual, visual selection RT, VRT, visual response speed, ART, auditory RT, wire maze tracing, Archimedes spiral, crisis tracking task, trajectory creation, tracking composite, tracking Wiener device, closure flexibility, WAIS block planning, WAIS picture comparison, digit copying, manipulative motion,These include fine motor skills, handwriting analysis, tapping, lateral reach and coordination of the hand and arm, visual random reach of the arm, motor control and coordination, and motor behavior.

[0037] According to several embodiments, the desired effects address symptoms such as pain, migraines, depression, cognitive impairment, attention deficit, hyperactivity, anxiety disorders, diarrhea, nausea, vomiting, insomnia, delirium, changes in appetite, sexual dysfunction, spasticity, increased intraocular pressure, bladder dysfunction, tics, Tourette's syndrome, post-traumatic stress disorder (PTSD) symptoms, inflammatory bowel disease (IBD) symptoms, irritable bowel syndrome (IBS) symptoms, excessive tension, bleeding symptoms, sepsis and cardiogenic shock, drug dependence and cravings, withdrawal symptoms, tremors, and other motor disorders.

[0038] According to some embodiments, the PD effect is a psychoactive effect and / or a physical effect.

[0039] According to some embodiments, the psychoactive effects respond to symptoms such as paranoia, anxiety, panic attacks, euphoria, pseudo-hallucinations, ataxia, sedation, altered conscious perception, cheerfulness, metacognition and introspection, facilitated recollection (episodic memory), amnesia, sensual alterations, altered sensory awareness and libido alterations, dizziness, ataxia, euphoria, altered perception, temporal distortion, intensification of normal sensory experiences, short-term memory, attention, impaired reaction, proficiency in activities, speech fluency, addiction and depression.

[0040] According to some embodiments, the physical effects respond to symptoms such as nausea, muscle contraction, muscle relaxation, convulsions, spasms, sweating, ataxia, changes in motor activity, thirst, coldness and heat in the hands and feet, increased heart rate, increased cerebral blood flow, bronchodilation, vasodilation, conjunctival congestion and pupil dilation, thirst, hunger, or craving for food.

[0041] According to some embodiments, the method presented herein is a method for delivering at least a first pharmacologically active agent and a second pharmacologically active agent to a subject in the lungs, at least one of which is present in at least one plant material, and the method includes the step of delivering the agents separately to the subject using an apparatus configured to vaporize at least a first predetermined vaporization amount of the first agent and at least a second predetermined vaporization amount of the second agent, wherein heating is performed so that the first predetermined vaporization amount is delivered to the subject in a continuous, simultaneous, and / or at least partially overlapping manner with the second predetermined vaporization amount.

[0042] According to some embodiments, the plants include Cannabis sativa, Cannabis indica, Cannabis ruderalis, Acacia spp., Amanita muscaria, Yage, Atropa belladonna, Areca catechu, Brugmansia spp., Brunfelsia latifolia, Desmanthus illinoensis, Banisteriopsis caapi, Trichocereus spp., Theobroma cacao, Capsicum spp., and Cestrum. spp.), Erythroxylum coca, Coleus (Solenostemon scutellarioides), Arundo donax, Coffea arabica, Datura spp., Desfontainia spp., Diplopterys cabrerana, Ephedra sinica, Claviceps purpurea, Paullinia cupana, Argyreia nervosa, Hyoscyamus niger, Tabernanthe iboga, Lagochilus inebriens, Justicia pectrali *Pectoralis*, *Sceletium tortuosum*, *Piper methysticum*, *Catha edulis*, *Mitragyna speciosa*, *Leonotis leonurus*, *Nymphaea* spp., *Nelumbo* spp.), Texas mountain laurel (Sophora secundiflora), red bean (Mucuna pruriens), mandrake (Mandragora officinarum), mimosa tenuiflora, yellow beach morning glory (Ipomoea violacea), Psilocybe spp., laughing mushroom (Panaeolus spp.), nutmeg (Myristica fragrans), Turbina corymbosa, passionflower (Passiflora incarnata), Lophophora williamsii, Phalaris spp., Pichuli (Duboisia hopwoodii), poppy (Papaver somniferum), Psychotria viridis species Viridis spp.), Salvia divinorum, Combretum quadrangulare, Trichocereus pachanoi, Heimia salicifolia, Stipa robusta, Solandra spp., Hypericum perforatum, Peganum harmala, Tabernaemontana spp., Camellia sinensis, Nicotiana tabacum, rusticum, Virola theidora, Voacanga africana, Lactuca virosa, Artemisia absinthium), mate (Ilex paraguariensis), Anadenanthera species (Anadenanthera spp.), yohimbe (Corynanthe yohimbe), Kalea (Calea zacatechichi), coffee plant (Coffea spp.)(Rubiaceae), Sapindaceae, Camellia spp., Malvaceae spp., Aquifoliaceae spp., Hoodia spp., German chamomile (Chamomilla recutita), Passiflora incarnate, Tea plant (Camellia sinensis), Peppermint (Mentha piperita), Spearmint (Mentha spicata), European raspberry (Rubus idaeus), Eucalyptus globulus, Lavandula officinalis, Thymus vulgaris, Lemon balm (Melissa officinalis), Aloe vera (Aloe) Vera, angelica, anise, ayahuasca (Banisteriopsis caapi), barley, black mint, blue lotus, burdock, chamomile, caraway, cat's claw, clove, comfrey, corn silk, ryegrass, damiana, damiana, dandelion, ephedra, eucalyptus, evening primrose, fennel, feverfew, fringe tree, garlic, ginger, ginkgo, ginseng, goldenrod, hydrastis, jar Examples include grass, green tea, guarana, hawthorn, hops, horsetail, hyssop, cola nuts, kraton, lavender, lemon balm, licorice, lion's tail (wild daga), maca bulbs, hollyhock, meadowsweet, milk thistle, motherwort, passionflower, passionflower, peppermint, thistle poppy, purslane, raspberry leaves, poppy, sage, saw palmetto, Sida cordifolia, Maya sunopener, spearmint, sweet flag, Syrian rue (Peganum harmala), thyme, turmeric, valerian, wild yam, wormwood, yarrow, mate, yohimbe, and any part or combination of these.

[0043] According to some embodiments, the plants include Cannabis sativa, Cannabis indica, and Cannabis ruderalis.

[0044] According to some embodiments, the pharmacologically active agent is Δ 9 Examples include tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), cannabinodiol (CBDL), cannabicyclol (CBL), cannabiersoin (CBE), cannabidivarin (CBDV), tetrahydrocannabivarin (THCV), and cannabitriol (CBT).

[0045] According to some embodiments, the pharmacologically active agent is Δ 9 - Examples include tetrahydrocannabinol (THC) and cannabidiol (CBD).

[0046] According to one embodiment of the present disclosure, a system is provided for delivering at least one pharmacologically active agent present in a plant material to a subject via the lungs, the system being: A quantitative inhalation device configured to vaporize at least one predetermined amount of a drug when a plant material is heated in a controllable manner; and A controller that communicates with the inhalation device, configured to select at least one predetermined vaporization amount of the drug in order to achieve at least one predetermined PK effect and / or at least one predetermined PD effect induced by the drug in the subject. It is equipped with.

[0047] According to one aspect of several embodiments of the present disclosure, a method is provided for delivering at least a first pharmacologically active agent and a second pharmacologically active agent to a subject through the lungs, wherein at least one of these agents is present in at least one plant material, and the method includes the step of separately delivering the agents to a subject using a metering inhaler configured to vaporize at least a first predetermined vaporization amount of the first agent and at least a second predetermined vaporization amount of the second agent when the plant material is controlledly heated, wherein the heating is performed so that the first predetermined vaporization amount is delivered to the subject sequentially, simultaneously, and / or at least partially overlapping with the second predetermined vaporization amount, and each of the predetermined vaporization amounts of the agent separately induces at least one predetermined pharmacokinetic (PK) effect and / or at least one predetermined pharmacodynamic (PD) effect in the subject.

[0048] According to some embodiments, the time interval between the delivery of the first drug and the delivery of the second drug is in the range of 0 to 30 minutes.

[0049] According to some embodiments, PD effects include desirable effects, undesirable effects, therapeutic effects, adverse effects, and biomarker levels.

[0050] According to some embodiments, a predetermined vaporization amount of the first agent affects the level of the PD effect induced by the second agent.

[0051] According to some embodiments, a predetermined vaporization amount of the first agent increases the level of the desired effect induced by the second agent.

[0052] According to some embodiments, a predetermined vaporization amount of the first agent reduces the level of undesirable effects induced by the second agent.

[0053] According to some embodiments, the first and second drugs synergistically induce the desired effect.

[0054] According to some embodiments, each predetermined vaporization amount of each drug is selected to achieve at least one predetermined PK effect and / or at least one predetermined PD effect that each drug separately induces in the subject.

[0055] According to some embodiments, each predetermined vaporization amount of the drug is determined based on at least one PK effect and / or at least one PD effect with respect to the population.

[0056] According to some embodiments, the method further includes the step of adjusting at least one of a first predetermined vaporization rate and a second predetermined vaporization rate to achieve a predetermined PK effect and / or predetermined PD effect based on data showing that the drug induces at least one PK effect and / or at least one PD effect in a subject.

[0057] According to some embodiments, the method further includes the step of generating data by monitoring at least one PK effect and / or at least one PD effect induced in a subject by at least one of the first and second drugs.

[0058] According to some embodiments, the method further includes the step of delivering at least one of two predetermined vaporization amounts of a first drug and a second drug to the lungs according to a predetermined regimen.

[0059] According to some embodiments, the method further includes a step of adjusting the regimen to achieve a predetermined PK effect and / or predetermined PD effect based on at least one PK effect and / or at least one PD effect induced in a subject by at least one of the first and second drugs.

[0060] According to some embodiments, the method further includes the step of generating data by monitoring at least one PK effect and / or at least one PD effect induced in a subject by at least one of the first and second drugs.

[0061] According to some embodiments, monitoring of PK effects and / or PD effects is performed at predetermined time intervals before, during, and / or after lung delivery.

[0062] According to some embodiments, monitoring includes the step of receiving data indicating at least one type of PD effect in a subject from at least one sensor communicating with a controller accompanied by an inhalation device.

[0063] According to some embodiments, the adjustment process is based on data received via a user interface device.

[0064] According to some embodiments, the adjustment process is performed in real time.

[0065] According to some embodiments, monitoring of PK effects and / or PD effects induced by at least one of the first and second drugs in the subject is performed at predetermined time intervals before, during, and / or after lung delivery.

[0066] According to some embodiments, the PK effect includes the concentration of each drug in a given volume of body fluid and the concentration of each drug in a given mass of body tissue.

[0067] According to some embodiments, the PD effect is related to a predetermined PD profile that lies within a range between the minimum level of a desirable effect and the level of an undesirable effect.

[0068] According to some embodiments, a given PD profile lies in a range between the minimum level of desirable effect and the minimum level of undesirable effect.

[0069] According to some embodiments, a given PD profile lies in a range between a minimum level of desirable effect and a minimum level of undesirable effect.

[0070] According to some embodiments, the step of determining at least one of the desired and / or undesirable effects includes the step of receiving instructions from the subject.

[0071] According to some embodiments, biomarkers include invasively detected biomarkers and non-invasively detected biomarkers.

[0072] According to some embodiments, non-invasively detected biomarkers include heart rate, oxygenation level (SpO2), blood pressure, respiratory rate, body temperature, inhalation volume, facial expression, muscle contraction, convulsions, spasms, sweating, hand-visual coordination, ocular vasodilation, conjunctival and / or scleral redness, intraocular pressure fluctuations, motor ability, ataxia, sinus tachycardia, tremor, cardiac arrhythmia, skin conductance / impedance level, seizures, electromyography (EMG), electrocardiogram (ECG), photoplethysmography (PPG), galvanic skin response (GSR), blue-brown visual inhibition, H-mask visual inhibition, auditory latent inhibition, visual latent inhibition, Stroop color word, simple response (conflict task), cognitive set switching, logical reasoning, decision time, rapid information processing, perceptual maze, simulated driving, visual search, time estimation, time perception, visual search, attentional search, symbol copying, letter cancellation, alphabet deletion, D2 cancellation, Brickenkamp D2, digit copying test (DDCT), symbol-digit substitution test (SDST), digit-symbol substitution test (DSST), digit vigilance, vigilance, auditory vigilance test, Wesness / Warburton vigilance task, rapid information processing, CRT + tracking split attention, selective attention, focused attention task, emotional attention task, auditory flutter Fusion, Flash Fusion, Critical Flicker Fusion (CFF), Attention Continuation, Paired Associative Learning, Word List Learning, 15-Word Test, Introduction Adjustment, Delayed Word Retrieval, Delayed Word Recognition, Delayed Picture Recognition, Word Presentation, Word Recognition, Numerical Working Memory, Numerical Memory, Memory Scanning, Auditory Brown / Peterson, Visual Brown / Peterson, Visuospatial Memory, Fragment Picture Test, Pauli Test, Block Span, Number Span, Number Span (Front), Number Span (Back), WAIS Vocabulary, WAIS Similarity, Word Fluency, Verbal Fluency, Performance Time (Delayed Word Recognition), Performance Time ( Numerical working memory, performance time (digital alertness), performance time (rapid information processing), performance time (delayed image recognition), performance time (visual information processing), simple reaction time CRT, composite RT visual, visual selection RT, VRT, visual response speed, ART, auditory RT, wire maze tracing, Archimedes spiral, crisis tracking task, trajectory creation, tracking composite, tracking Wiener device, closure flexibility, WAIS block planning, WAIS image comparison, digit copying, manipulative motor skills, fine motor skills, handwriting analysis, tapping, hand-arm lateral reach alignment, visual arm random reach.This includes motor control and coordination, and motor behavior.

[0073] According to some embodiments, the desired effects are in response to symptoms such as pain, migraines, depression, cognitive impairment, attention deficit, hyperactivity, anxiety disorders, diarrhea, nausea, vomiting, insomnia, delirium, changes in appetite, sexual dysfunction, spasticity, increased intraocular pressure, bladder dysfunction, tics, Tourette's syndrome, post-traumatic stress disorder (PTSD) symptoms, inflammatory bowel disease (IBD) symptoms, irritable bowel syndrome (IBS) symptoms, excessive tension, bleeding symptoms, sepsis and cardiogenic shock, drug dependence and cravings, withdrawal symptoms, tremors, and other motor disorders.

[0074] According to some embodiments, the PD effect is a psychoactive effect and / or a physical effect.

[0075] According to some embodiments, the psychoactive effects respond to symptoms such as paranoia, anxiety, panic attacks, euphoria, pseudo-hallucinations, ataxia, sedation, altered conscious perception, cheerfulness, metacognition and introspection, facilitated recollection (episodic memory), amnesia, sensual alterations, altered sensory awareness and libido alterations, dizziness, ataxia, euphoria, altered perception, temporal distortion, intensification of normal sensory experiences, short-term memory, attention, impaired reaction, proficiency in activities, speech fluency, addiction and depression.

[0076] According to some embodiments, the physical effects respond to symptoms such as nausea, muscle contraction, muscle relaxation, convulsions, spasms, sweating, ataxia, changes in motor activity, thirst, coldness and heat in the hands and feet, increased heart rate, increased cerebral blood flow, bronchodilation, vasodilation, conjunctival congestion and pupil dilation, thirst, hunger, or craving for food.

[0077] According to some embodiments, at least one plant species may include Cannabis sativa, Cannabis indica, Cannabis ruderalis, Acacia, Amanita muscaria, Yahe, Belladonna, Betel nut, Brugmansia, Brunfelsia japonica, Aster tataricus, Banisteriopsis carpi, Trichocereus, Cacao, Capsicum, Cestrum, Cocaine, Coleus, Aruncus dioicus, Coffee plant, Datura, Desfontainea, Dipropterus cabrerana, Euonymus sinensis, Baccaratum, Guarana, Ipomoea purpurea, Hemerocallis fulva, and Wart. Moth, Lagochylus inebrians, Justicia pectralis, Selenium tortosum, Kawakawa, Arabian tea tree, Opium tree, Flame lily, Nymphaea, Nelumbo, Texas mountain laurel, Lime bean, Mandragora, Mimosa tenuiflora, Yellow beach morning glory, Psilocybe, Laughing mushroom, Nutmeg, Turvina colibosa, Passiflora, Phragmites, Phragmites, Pichuli, Poppy, Psychotria viridis, Salvia divinorum, Sakena, Trichocereus pachanoi, Sinikui, Sleepy grass, Solandra, St. John's wort, Harmala, Trifoliate orange, Camellia, Nicotiana tabacum, Rusticum, Virola seidra, Boacantha africana, Wild lettuce, Wormwood, Yerba mate, Ana denanthera, Yohimbe, Kalea, Coffea (Rubiaceae), Sapindaceae, Camellia, Malvaceae, Aquifoliaceae, Hoodia, German chamomile, Passiflora incarnate, Camellia, Peppermint, Spearmint, Raspberry, Eucalyptus, Lavender, Thyme, Lemon balm, Aloe vera, Angelica Ka, anise, ayahuasca (banisteriopsis carpi), barley, black mint, blue lotus, burdock, chamomile, caraway, cat's claw, clove, comfrey, corn silk, ryegrass, damiana, damiana, dandelion, ephedra, eucalyptus, evening primrose, fennel, feverfew, fringe tree, garlic, ginger, ginkgo, ginseng, goldenrod, hydrastis, sedge, green tea, guarana, hawthorn, hops, horsetail, hyssop, cola nut, craton, lavender, lemon balm, licorice,Lion's tail (wild dagga), maca root, Usbenitachiaoi, Shimotsukesou, Great thistle, Mehajiki, Passion flower, Aloe vera, Peppermint, Azamigesi, Sberihiyu, Raspberry leaf, Coccinia grandis, Sage, Saw palmetto, Malva kinko deer, Shinikuichi (Mayan sun opener), Spearmint, Sweet flag, Syrian rue (Peganum harmala), Thyme, Turmeric, Kanokoso, Wild yam, Japanese mugwort, Sawtooth, Mate, Yohimbine, and any part and any combination thereof are included.

[0078] According to some embodiments, at least one plant includes Cannabis sativa, Cannabis indica, and Cannabis ruderalis.

[0079] According to some embodiments, at least one of the first pharmacologically active agent and the second pharmacologically active agent includes Δ 9 -tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerol (CBG), cannabinchrome (CBC), cannabinol (CBN), cannabidivarin (CBDL), cannabicyclol (CBL), cannabielsoin (CBE), cannabidiovaline (CBDV), tetrahydrocannabivarin (THCV), and cannabinatriol (CBT).

[0080] According to some embodiments, at least one of the first pharmacologically active agent and the second pharmacologically active agent includes Δ 9 -tetrahydrocannabinol (THC) and cannabidiol (CBD).

[0081] According to one aspect of some embodiments of the present disclosure, a system for pulmonary delivery of at least a first pharmacologically active agent and a second pharmacologically active agent to a subject is provided, at least one of these agents is present in at least one plant-based material, and the system includes: A metered-dose inhalation device configured to deliver drugs separately to a subject by heating at least one plant material to vaporize at least a first predetermined vaporization amount of a first drug and at least a second predetermined vaporization amount of a second drug; and A controller communicating with an inhalation device configured to perform heating of a first predetermined vaporization amount that is continuous with, simultaneously with, and / or at least partially overlapping with, a second predetermined vaporization amount. Equipped with, The predetermined vaporization amount for each of the drugs is selected so as to separately induce at least one PK effect and / or at least one PD effect in the subject.

[0082] According to one aspect of several embodiments of this disclosure, a system is provided, and the system is: A quantitative inhalation device for delivering at least one pharmacologically active drug in a predetermined vaporized amount from a plant material to a subject's lungs by controllingly heating the plant material to vaporize at least one drug in a predetermined vaporized amount; and A controller that communicates with an inhalation device configured to control a predetermined vaporization rate based on data showing at least one pharmacodynamic effect induced by the drug in the subject. It is equipped with.

[0083] According to some embodiments, data is obtained via at least one sensor configured to monitor pharmacodynamic effects and / or via a user interface device configured to input data obtained from at least one sensor for monitoring pharmacodynamic effects.

[0084] According to some embodiments, the controller is configured to receive operation setting data regarding a predetermined vaporization amount from a remote control device.

[0085] According to some embodiments, the controller is configured to receive data from sensors and / or user interface devices.

[0086] According to some embodiments, the controller communicates directly and / or indirectly with sensors and / or interface devices.

[0087] According to some embodiments, the controller is configured to control a predetermined vaporization amount by controlling at least one of the following: airflow, heating temperature, heating rate, heating pattern, heating time, and any combination thereof.

[0088] According to some embodiments, the controller is configured to control a predetermined vaporization amount by controlling the timing of lung delivery.

[0089] According to some embodiments, the control process is performed in real time.

[0090] According to some embodiments, the controller is configured to adjust a predetermined vaporization rate to achieve a predetermined pharmacokinetic effect and / or predetermined pharmacodynamic effect based on pharmacodynamic effects.

[0091] According to some embodiments, the controller is configured to perform adjustments to a predetermined vaporization rate in real time.

[0092] According to some embodiments, the controller is configured to perform a predetermined regimen that includes the delivery of at least two predetermined vaporization amounts.

[0093] According to some embodiments, the controller is configured to adjust the regimen to achieve a predetermined pharmacokinetic effect and / or predetermined pharmacodynamic effect based on pharmacodynamic effects.

[0094] According to some embodiments, the controller is configured to perform regime adjustments in real time.

[0095] According to some embodiments, the system comprises at least one sensor configured to monitor pharmacodynamic effects.

[0096] According to some embodiments, the system includes a user interface device.

[0097] According to some embodiments, the user interface device includes an output device that provides information to at least one of a subject, a physician, a memory unit, and a remote device.

[0098] According to some embodiments, the user interface device includes a smartphone device.

[0099] According to some embodiments, the controller is configured to monitor at least one of at least one predetermined pharmacokinetic effect and / or at least one predetermined pharmacodynamic effect based on data received via a user interface device.

[0100] According to some embodiments, the controller is configured to perform adjustments to a predetermined vaporization rate in real time.

[0101] According to some embodiments, the sensor comprises a touchscreen, accelerometer, proximity sensor, infrared sensor, camera, magnetometer, user position and orientation sensor, gyroscope, compass, microphone, thermometer, humidity sensor, heart rate sensor, blood pressure sensor, skin conductance / impedance sensor, blood oxygenation level (SpO2), inhalation volume sensor, and airflow sensor.

[0102] According to some embodiments, the system comprises at least one dose unit, which contains a plant material.

[0103] According to some embodiments, the system comprises multiple dose units, and the inhaler is configured to use at least one of the dose units.

[0104] According to some embodiments, each dose unit contains a plant material having a different composition of at least one pharmacologically active agent.

[0105] According to some embodiments, the controller is configured to control a predetermined vaporization amount by selecting at least one dose unit according to the composition of at least one pharmacologically active agent.

[0106] According to some embodiments, the inhalation device is configured to deliver at least a first pharmacologically active agent and a second pharmacologically active agent to a subject's lungs by a controller, wherein at least one of these agents is present in at least one plant material, and the device is configured to vaporize at least a first predetermined vaporization amount of the first agent and at least a second predetermined vaporization amount of the second agent, wherein heating is performed to deliver the first predetermined vaporization amount to the subject continuously, simultaneously, and / or in overlapping manner with the second predetermined vaporization amount.

[0107] According to some embodiments, the plants include Cannabis sativa, Cannabis indica, Cannabis ruderalis, Acacia, Amanita muscaria, Yahe, Belladonna, Betel nut, Brugmansia, Brunfelsia japonica, Sedum sieboldii, Banisteriopsis carpi, Trichocereus, Cacao, Capsicum, Cestrum, Cocaine, Coleus, Aruncus dioicus, Coffee plant, Datura, Desfontainea, Dipropterus cabrerana, Euphorbia sinensis, Baccaratum, Guarana, Ipomoea purpurea, Hemerocallis fulva, Ipomoea purpurea, Lagochrysum sieboldii Brians, Justicia pectralis, Selenium tortosum, Kawakawa, Arabian tea, Opium tree, Flame lily, Nymphaea, Nelumbo, Texas mountain laurel, Lime bean, Mandragora, Mimosa tenuiflora, Yellow beach morning glory, Psilocybe, Laughing mushroom, Nutmeg, Turvina colibosa, Passiflora, Phragmites, Phragmites, Pichuli, Poppy, Psychotria viridis, Salvia divinorum, Sakena, Trichocereus pachanoi, Sinikui, Sleepy grass, Solandra, European St. John's wort, Harmala, Trifoliate orange, Camellia sinensis, Nicotiana tabacum, Rusticum, Virola seidra, Boacantha africana, Wild lettuce, Wormwood, Yerba mate, Ana denanthera species, Yohimbe, Kalea, Coffea (Rubiaceae), Sapindaceae, Camellia, Malvaceae, Aquifoliaceae, Hoodia, German chamomile, Passiflora incarnate, Camellia sinensis, Peppermint, Spearmint, European raspberry, Eucalyptus, Lavender, Thyme, Lemon balm, Aloe vera, Angelica, Anise, Ayahuasca (Banisteriopsis carpi), Berberis, Black mint, Blue lotus, Burdock, Chamomile, Caraway, Cat's claw, Clove, Comfrey, Corn silk, Ryegrass, Damiana, Damiana, Dandelion, Ephedra, Eucalyptus, Evening primrose, Fennel, Feverfew, American fringe tree, Garlic, Ginger, Ginkgo biloba, Korean ginseng, Goldenrod, Hydrastis, Potentilla, Green tea, Guarana, Hawthorn, Hops, Horsetail, Hyssop, Cola nut, Craton, Lavender, Lemon balm, Licorice, Lion's tail (wild daga),Examples include maca bulbs, hollyhock, meadowsweet, milk thistle, motherwort, passionflower, passionflower, peppermint, thistle poppy, purslane, raspberry leaves, poppy, sage, saw palmetto, dwarf yam, cinquefoil (Maya sunopener), spearmint, sweet flag, Syrian rue (Peganum harmara), thyme, turmeric, valerian, wild yam, wormwood, yarrow, mate, yohimbe, and any part or combination thereof.

[0108] According to some embodiments, the plants include Cannabis sativa, Cannabis indica, and Cannabis ruderalis.

[0109] According to some embodiments, the pharmacologically active agent is Δ 9 Examples include tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), cannabinodiol (CBDL), cannabicyclol (CBL), cannabiersoin (CBE), cannabidivarin (CBDV), tetrahydrocannabivarin (THCV), and cannabitriol (CBT).

[0110] According to some embodiments, the pharmacologically active agent is Δ 9 - Examples include tetrahydrocannabinol (THC) and cannabidiol (CBD).

[0111] According to one aspect of several embodiments of the present disclosure, a method is provided for delivering at least one pharmacologically active agent present in a plant material to a subject via the lungs; the method includes; A process of delivering a drug to a subject's lungs from a quantitative inhalation device configured to vaporize at least one predetermined amount of drug when a plant material is controlledly heated; A step of monitoring at least one pharmacokinetic effect and / or at least one pharmacodynamic effect induced by the drug in a subject; The process includes adjusting at least one predetermined vaporization amount to achieve at least one predetermined pharmacokinetic effect and / or at least one predetermined pharmacodynamic effect based on data obtained through monitoring.

[0112] According to one aspect of several embodiments of the present disclosure, a method is provided for recording at least one pharmacokinetic and / or at least one pharmacodynamic effect induced by delivering at least one pharmacologically active agent present in a plant material to a subject via lung delivery; the method includes; A process of delivering a predetermined amount of a drug to a subject's lungs from a quantitative inhalation device configured to vaporize a predetermined amount of the drug when a plant-based material is heated in a controllable manner; If necessary, a step of determining at least one pharmacokinetic effect in the subject before, during, and / or after lung delivery at predetermined time intervals; The process includes determining at least one pharmacodynamic effect in a subject at predetermined time intervals before, during, and / or after lung delivery; Pharmacodynamic effects include desirable effects, undesirable effects, therapeutic effects, adverse effects, and biomarker levels.

[0113] According to one aspect of several embodiments of the present disclosure, a method is provided for delivering at least one pharmacologically active drug to a patient (hereinafter referred to herein interchangeably with "test user") into the lungs, the method comprising the step of delivering the drug to the patient from a metering inhaler configured to release at least one predetermined vaporized amount of the drug when a solid substance containing the drug is controlledly heated, the method comprising selecting at least one predetermined vaporized amount of the drug such that the patient exhibits at least one pre-selected pharmacokinetic profile and / or at least one pre-selected pharmacodynamic profile of the drug.

[0114] According to some embodiments, the method further includes: A step of determining at least one pharmacokinetic parameter and / or at least one pharmacokinetic variable and / or at least one pharmacodynamic parameter induced by delivering the drug to the patient's lungs from the device; A step of determining a predetermined vaporization volume that exhibits a pre-selected pharmacokinetic profile and / or pre-selected pharmacodynamic profile of the drug in a patient, based on the above pharmacokinetic parameters and / or pharmacokinetic variable elements and / or pharmacodynamic parameters; and The process includes configuring the device to deliver at least one predetermined vaporized amount of a drug.

[0115] According to some embodiments of any of the embodiments described herein, each of the pharmacokinetic parameters and / or pharmacokinetic variable elements and / or pharmacodynamic parameters is determined for individual patients so that a predetermined vaporization volume is individually determined for each patient.

[0116] According to some embodiments of any of the embodiments described herein, lung delivery includes: A step of determining the pharmacodynamic and / or pharmacokinetic parameters of at least one individual in an individual patient in order to determine whether the pulmonary delivery of at least one predetermined vaporized amount of drug exhibits a pre-selected pharmacodynamic and / or pre-selected pharmacokinetic profile in the individual patient; If the pulmonary delivery of at least one predetermined vaporized amount of drug does not exhibit a pre-selected pharmacodynamic and / or pharmacokinetic profile in the individual patient, the step of determining an adjusted vaporized amount of drug that exhibits a pre-selected pharmacodynamic and / or pharmacokinetic profile in the individual patient; and The process includes reconfiguring the device that delivers the above-mentioned adjusted vaporization amount. As a result, the adjusted vaporization amount becomes the predetermined vaporization amount during reconstruction.

[0117] According to some embodiments of the embodiments described herein, the individual's pharmacodynamic parameters are selected from the group consisting of the therapeutic effect perceived by the individual, the adverse effect perceived by the individual, and the presence or absence of biomarkers.

[0118] According to some embodiments of any of the embodiments described herein, the biomarker is selected from the group consisting of invasively detected biomarkers and non-invasively detected biomarkers.

[0119] According to some embodiments of any of the embodiments described herein, non-invasively detected biomarkers include heart rate, oxygenation level (SpO2), blood pressure, respiratory rate, body temperature, inhalation volume, facial expression, muscle contraction, convulsions, spasms, sweating, hand-visual coordination, ocular vasodilation, conjunctival and / or scleral redness, intraocular pressure fluctuations, motor function, ataxia, sinus tachycardia, tremor, cardiac arrhythmia, skin conductance / impedance levels, seizures, electromyography (EMG), electrocardiogram (ECG), photoplethysmography (PPG), galvanic skin response (GSR), blue-brown vision inhibition, and H-mask vision. Inhibition, auditory latent inhibition, visual latent inhibition, Stroop color word, simple response (conflict task), cognitive set switching, logical reasoning, decision time, rapid information processing, perceptual maze, simulated driving, visual search, time estimation, time perception, visual search, attentional search, symbol copying, letter cancellation, alphabet deletion, D2 cancellation, Brickenkamp D2, digit copying test (DDCT), symbol-digit substitution test (SDST), digit-symbol substitution test (DSST), digit vigilance, vigilance, auditory vigilance test, Wesness / Warburton vigilance task, rapid information processing, CRT + tracking segmented attention, selective attention, cluster Intermediate attention tasks, emotional attention tasks, auditory flutter fusion, flash fusion, critical flicker fusion (CFF), attention continuity, paired associative learning, word list learning, 15-word test, introduction adjustment, delayed word recall, delayed word recognition, delayed picture recognition, word presentation, word recognition, numerical working memory, numerical memory, memory scanning, auditory Brown / Peterson, visual Brown / Peterson, visuospatial memory, fragment picture test, Pauli test, block span, number span, number span (forward), number span (backward), WAIS vocabulary, WAIS similarity, word fluency, verbal fluency, performance time Delayed word recognition, performance time (numerical working memory), performance time (digital alertness), performance time (rapid information processing), performance time (delayed picture recognition), performance time (visual information processing), simple reaction time CRT, composite RT visual, visual selection RT, VRT, visual response speed, ART, auditory RT, wire maze tracing, Archimedes spiral, crisis tracking task, trajectory creation, tracking composite, tracking Wiener device, closure flexibility, WAIS block planning, WAIS picture comparison, digit copying, manipulative motor skills, fine motor skills, handwriting analysis, tapping,The group is selected from the following: lateral reach coordination of the hand and arm, visual random reach of the arm, motor control and coordination, and motor behavior.

[0120] According to some embodiments of any of the embodiments described herein, the therapeutic effect perceived by an individual responds to symptoms selected from the group consisting of pain, migraine, depression, cognitive impairment, attention deficit, hyperactivity, anxiety disorder, diarrhea, nausea, vomiting, insomnia, delirium, changes in appetite, sexual dysfunction, spasticity, increased intraocular pressure, bladder dysfunction, tics, Tourette's syndrome, post-traumatic stress disorder (PTSD) symptoms, inflammatory bowel disease (IBD) symptoms, irritable bowel syndrome (IBS) symptoms, excessive tension, bleeding symptoms, sepsis and cardiogenic shock, drug dependence and cravings, withdrawal symptoms, tremors and other movement disorders.

[0121] According to some embodiments of any of the embodiments described herein, the adverse effects perceived by an individual are psychoactive adverse effects and / or physical adverse effects.

[0122] According to some embodiments of any of the embodiments described herein, the psychoactive adverse effects respond to symptoms selected from the group consisting of paranoia, anxiety, panic attacks, euphoria, pseudo-hallucinations, ataxia, sedation, altered conscious perception, cheerfulness, metacognition and introspection, facilitated recollection (episodic memory), amnesia, sensual alterations, altered sensory awareness and libido alterations, dizziness, ataxia, euphoria, altered perception, temporal distortion, intensification of normal sensory experiences, short-term memory, attention, impaired response, proficiency in activities, speech fluency, addiction, and depression.

[0123] According to some embodiments of any of the embodiments described herein, the physical adverse effects are in response to symptoms selected from the group consisting of nausea, muscle contraction, muscle relaxation, convulsions, spasms, sweating, ataxia, altered motor activity, dry mouth, and coldness and heat in the hands and feet, increased heart rate, increased cerebral blood flow, bronchodilation, vasodilation, conjunctival hyperemia and pupil dilation, dry mouth, thirst, hunger or craving for food.

[0124] According to some embodiments of any of the embodiments described herein, lung delivery is further: The process includes configuring a device for delivering a controlled vaporization amount of a drug, wherein the controlled vaporization amount is selected to exhibit a re-selected pharmacodynamic profile of the drug in the patient. Therefore, in this configuration, the adjusted vaporization amount is a predetermined vaporization amount, and the re-selected pharmacodynamic profile is the pre-selected pharmacodynamic profile.

[0125] According to some embodiments of any of the embodiments described herein, the apparatus is configured to deliver a predetermined vaporization amount such that the deviation of the actual vaporization amount of the agent from a predetermined vaporization amount of the agent is less than 20% of the predetermined vaporization amount.

[0126] According to some embodiments of any of the embodiments described herein, the deviation of the actual pharmacokinetic profile from a pre-selected pharmacokinetic profile is less than 40% of the pre-selected pharmacokinetic profile.

[0127] According to some embodiments of any of the embodiments described herein, the deviation of the perceived pharmacodynamic profile from a pre-selected pharmacodynamic profile at at least one time point is less than 25% of the pre-selected pharmacodynamic profile.

[0128] According to some embodiments of the embodiments described herein, the pre-selected pharmacodynamic profile is: Pharmacodynamic profiles in the range below the minimum level of therapeutic effect, A pharmacodynamic profile that falls within the range from the minimum level of therapeutic effect to the maximum level of therapeutic effect, in which no adverse effects are observed or perceived, and The group is selected from those whose pharmacodynamic profiles fall within a range higher than the minimum level of adverse effects.

[0129] According to some embodiments of any of the embodiments described herein, the pharmacodynamic profile is within the range of the minimum level of therapeutic effect in which no adverse effects are observed or perceived, and the maximum level of therapeutic effect (within the therapeutic window).

[0130] According to some embodiments of any of the embodiments described herein, the deviation of the perceived pharmacodynamic profile from a pre-selected pharmacodynamic profile at at least one time point is less than 25% of the pre-selected pharmacodynamic profile.

[0131] According to some embodiments of the embodiments described herein, the pharmacokinetic variable elements are selected from the group consisting of body weight, height, sex, age, body mass index, and lean body mass.

[0132] According to some embodiments of any of the embodiments described herein, the pharmacokinetic parameters are such that the maximum plasma concentration (C) max ), time to reach maximum plasma concentration (T max ) and total exposure over time (AUC 0→∞ Selected from the group consisting of ).

[0133] According to some embodiments of the embodiments described herein, pharmacokinetic and / or pharmacodynamic parameters are determined while monitoring at least one additional parameter selected from the group consisting of: Vital signs selected from the group consisting of heart rate, oxygenation level (SpO2), blood pressure, respiratory rate, and body temperature; Lung function selected from the group consisting of forced expiratory capacity (FEV1), maximum intermediate expiratory flow rate (MMEF), carbon monoxide pulmonary diffusion capacity (DLCO), forced vital capacity (FVC), total lung volume (TLC), and residual lung volume (RV); Hematological markers selected from the group consisting of hemoglobin level, hematocrit ratio, red blood cell count, white blood cell count, white blood cell differential, and platelet count; Coagulation parameters selected from the group consisting of prothrombin time (PT), prothrombin ratio (PR), and international normalized ratio (INR); Renal function markers selected from the group consisting of creatinine clearance (CCr), blood urea nitrogen level (BUN), and glomerular filtration rate (GFR); and A liver function marker selected from the group consisting of aspartate aminotransferase (AST) levels, serum glutamate oxaloacetate transaminase (SGOT) levels, alkaline phosphatase levels, and gamma glutamyltransferase (GGT) levels.

[0134] According to some embodiments of any of the embodiments described herein, the method described herein is for delivering at least two pharmacologically active agents to a patient's lungs, and the device is configured to deliver each of the at least two pharmacologically active agents separately in predetermined vaporization amounts.

[0135] According to some embodiments of any of the embodiments described herein, the method is for delivering at least two pharmacologically active agents at predetermined time intervals.

[0136] According to some embodiments of any of the embodiments described herein, the method is for separately delivering at least two pharmacologically active agents in a predetermined vaporization amount, wherein the substance comprises at least two pharmacologically active agents.

[0137] According to some embodiments of any of the embodiments described herein, the method is for delivering a plurality of predetermined vaporization amounts of pharmacologically active agents, wherein the plurality of predetermined vaporization amounts are either identical or different from one another.

[0138] According to some embodiments of any of the embodiments described herein, a plurality of predetermined vaporization amounts are delivered from the device at the same or different predetermined time intervals.

[0139] According to some embodiments of any of the embodiments described herein, the device communicates with a patient interface circuit.

[0140] According to one aspect of several embodiments of the present disclosure, a metered-dose inhalation device is provided which is configured to deliver a predetermined vaporized amount of at least one pharmacologically active agent to a patient's lungs when a solid substance containing the agent is controlledly heated, wherein the device: The predetermined vaporization volume is the amount that exhibits a pre-selected pharmacokinetic profile and / or pre-selected pharmacodynamic profile in the patient; also, The predetermined vaporization amount of the drug is determined by determining at least one pharmacokinetic parameter and / or at least one pharmacokinetic variable and / or at least one pharmacodynamic parameter induced by the delivery of the drug from the device to the patient's lungs.

[0141] According to some embodiments of any of the embodiments described herein, the device is configured to communicate with a patient interface circuit.

[0142] According to some embodiments of any of the embodiments described herein, the device is capable of releasing a predetermined vaporization amount such that the deviation of the actual vaporization amount of the drug from a predetermined vaporization amount of the drug is less than 20% of the predetermined vaporization amount.

[0143] According to some embodiments of any of the embodiments described herein, the apparatus is capable of releasing a predetermined vaporization amount such that the deviation of the actual pharmacokinetic profile from a pre-selected pharmacokinetic profile is less than 40% of the pre-selected pharmacokinetic profile.

[0144] According to some embodiments of any of the embodiments described herein, the apparatus can release a predetermined amount of vapor such that the deviation of the perceived pharmacodynamic profile from a pre-selected pharmacodynamic profile at least one time point in time is less than 25% of the pre-selected pharmacodynamic profile.

[0145] According to some embodiments of any of the embodiments described herein, lung delivery, drug, predetermined vaporization volume, pre-selected pharmacokinetic profile and / or pre-selected pharmacodynamic profile of the drug in the patient, at least one pharmacokinetic parameter and / or at least one pharmacokinetic variable element and / or at least one pharmacodynamic parameter, re-selected pharmacodynamic profile, adjusted vaporization volume, and any determination thereof are as described in any one of the individual embodiments.

[0146] According to one aspect of several embodiments of the present disclosure, a patient interface circuit for use with a metered-dose inhalation device is provided, the device being configured to deliver a plurality of predetermined vaporized amounts of at least one pharmacologically active agent to a patient's lungs, the patient interface circuit being: controller; Input section; Equipped with a communication module: Multiple predetermined vaporization amounts are delivered from the device at predetermined time intervals, and these amounts and / or time intervals may be the same or different; Multiple predetermined vaporization amounts and predetermined time intervals include dosage, administration method and / or regimen, and the input unit is configured to receive dosage and / or regimen. The input unit is configured to interact with the patient in real time during drug delivery to obtain feedback from the patient; The controller is configured to iteratively partially modify the dose and / or regimen in accordance with feedback, thereby deriving an adjusted dose and / or regimen that includes an adjusted predetermined vaporization rate and an adjusted time interval; also The communication module is configured to communicate adjusted doses, adjusted dosing patterns, and / or adjusted regimens to the MDI device.

[0147] According to some embodiments of any of the embodiments described herein, the dose and / or regimen is selected to exhibit at least one pre-selected pharmacokinetic profile and / or at least one pre-selected pharmacodynamic profile of the drug in the patient.

[0148] According to some embodiments of any of the embodiments described herein, the patient interface circuit is configured on a personal portable device, a portable device, a wearable device, a wrist device, or an integrated eyewear device.

[0149] According to some embodiments of any of the embodiments described herein, the personal portable device is selected from the group consisting of a smartphone, a handheld device, a wearable device, a wrist device, or an integrated eyewear device.

[0150] According to some embodiments of any of the embodiments described herein, the patient interface circuit comprises a memory that communicates with a controller, and the memory is configured to store patient dose and / or regimen and usage data.

[0151] According to some embodiments of any of the embodiments described herein, the controller is configured to partially modify the dose and / or regimen in response to usage data.

[0152] According to some embodiments of any of the embodiments described herein, the patient interface circuit is configured to provide a toolset for obtaining at least one personal pharmacodynamic parameter and / or at least one personal pharmacokinetic parameter of a patient.

[0153] According to some embodiments of any of the embodiments described herein, the individual's pharmacodynamic parameters are selected from the group consisting of the therapeutic effects perceived by the individual, the adverse effects perceived by the individual, and biomarkers.

[0154] According to some embodiments of any of the embodiments described herein, the toolset comprises at least one interactive application for assisting a patient in linking the level of at least one therapeutic effect perceived by the individual and / or the level of adverse effects perceived by the individual and / or the level of a biomarker.

[0155] According to some embodiments of any of the embodiments described herein, the interactive application is gameware installed on a smartphone in which a patient interface is configured.

[0156] According to one aspect of several embodiments of this disclosure, a system is provided, and the system is: A quantitative inhalation device for delivering at least one pharmacologically active agent to a patient's lungs in a predetermined vaporization amount; and The device is equipped with a patient interface circuit that communicates with the device, At least one of the patient interface circuits and devices is configured to partially modify an operating setting in accordance with at least one type of direct and indirect input information received in real time from the patient using the device, the operating setting including a dose and / or regimen for delivering a drug to the patient's lungs.

[0157] According to some embodiments of any of the embodiments described herein, the system is configured to adjust operating settings while maintaining the dose and / or regimen within a patient-specific, individual safety range that prevents harm to the patient.

[0158] According to some embodiments of any of the embodiments described herein, the operational settings further include one or more protocols for coordinating the transfer of dosage and / or regimen and / or usage data between system components.

[0159] According to some embodiments of any of the embodiments described herein, the operating settings determine a time-coordinated schedule for the patient interface circuit to prompt the patient to use the device.

[0160] According to some embodiments of any of the embodiments described herein, the system comprises at least one sensor for measuring at least one individual pharmacodynamic parameter in a patient.

[0161] According to some embodiments of any of the embodiments described herein, the patient interface is configured on the individual's smartphone, and the sensors are standard components of the smartphone.

[0162] According to some embodiments of any of the embodiments described herein, the sensor is selected from the group consisting of a touchscreen, a camera, an accelerometer, and a microphone.

[0163] According to some embodiments of any of the embodiments described herein, the sensor is a flow sensor provided within the device, which is configured to detect the patient's inhalation volume in order to evaluate at least one individual pharmacodynamic parameter in the patient based on the correlation between the inhalation volume and the individual's pharmacodynamic parameters.

[0164] According to some embodiments of any of the embodiments described herein, the individual pharmacodynamic parameter that correlates with the inhalation volume is the pain level.

[0165] According to some embodiments of any of the embodiments described herein, direct input information includes intentional instructions provided by the patient using a patient interface circuit.

[0166] According to some embodiments of any of the embodiments described herein, indirect input information includes the therapeutic effects and / or adverse effects perceived by the individual, obtained from the patient through the patient interface circuit.

[0167] According to some embodiments of any of the embodiments described herein, the system further comprises a physician interface that communicates with a patient interface circuit and a device, the physician interface being configured to allow the physician to select the operating settings.

[0168] According to some embodiments of any of the embodiments described herein, the system further comprises a database server that communicates with at least one of the apparatus, a physician interface, and a patient interface circuit.

[0169] According to some embodiments of any of the embodiments described herein, the physician interface is configured to communicate with a database server to create patient doses and / or regimens, and the operational settings include doses and / or regimens.

[0170] According to some embodiments of any of the embodiments described herein, the operating settings are partially modified according to patient usage data.

[0171] According to some embodiments of any of the embodiments described herein, the apparatus comprises a substance dispenser configured to provide a drug, and a controller for activating the dispenser for lung delivery of the vaporized drug to a patient.

[0172] According to one aspect of several embodiments of the present disclosure, a method is provided for operating a metered-dose inhalation device configured to deliver at least one pharmaceutically active agent to a patient's lungs, the method comprising: A step of selecting a dose and / or regimen for delivering a drug to a patient's lungs using the device; The process includes obtaining real-time instructions regarding the pharmacodynamic effects and / or pharmacokinetic effects of at least one individual patient during drug delivery to the lungs; and automatically adjusting the dose and / or regimen according to those instructions. According to some embodiments of any of the embodiments described herein, the individual's pharmacodynamic parameters are selected from the group consisting of the therapeutic effects perceived by the individual, the adverse effects perceived by the individual, and biomarkers (presence and / or levels).

[0173] According to some embodiments of any of the embodiments described herein, the therapeutic effect perceived by the individual is a reduction in the level of symptoms, and the adverse effect perceived by the individual is a psychoactive effect and / or a physical adverse effect.

[0174] According to some embodiments of any of the embodiments described herein, the dose and / or regimen is pre-selected such that an initial accumulation of the drug is demonstrated in the patient, and / or that a pre-selected pharmacokinetic profile and / or pre-selected pharmacodynamic profile of the drug is maintained in the patient for a period of at least the same length as the drug lung delivery time.

[0175] According to some embodiments of any of the embodiments described herein (methods, apparatus, circuits, or systems), the apparatus is configured to deliver at least one predetermined vaporized amount of an agent when a solid substance containing the agent is controlledly heated.

[0176] According to some embodiments of any of the embodiments described herein (of methods, apparatus, circuits, or systems), the substance is a plant-based material.

[0177] According to some embodiments of any of the embodiments described herein (methods, apparatus, circuits, or systems), the plants include Cannabis sativa, Cannabis indica, Cannabis ruderalis, Acacia, Amanita muscaria, Yahe, Belladonna, Betel nut, Brugmansia, Brunfelsia, Aster tataricus, Banisteriopsis carpi, Trichocereus, Cacao, Capsicum, Cestrum, Cocaine, Coleus, Aruncus dioicus, Coffee plant, Datura, Desfontainea, Dipropteris cabrerana, and Euonymus sinensis. , buckwheat, guarana, morning glory, henbane, ragwort, Lagochilus inebrians, Justicia pectralis, Selenium tortosum, kawakawa, tea arabica, opium tree, flamingoose, water lily, lotus, Texas mountain laurel, red bean, mandrake, mimosa tenuiflora, yellow beach morning glory, pygmy mushroom, nutmeg, Turvina colibosa, passionflower, bellflower, Phragmites, pichurii, poppy, Psychotria viridis, Salvia divinorum, sakena, Trichocereus Us pachanoi, Sinikui, Sleepygrass, Solandra, St. John's wort, Harmala, Trifolium, Tea plant, Nicotiana tabacum, Rusticum, Virola seidra, Boacantha africana, Wild lettuce, Wormwood, Yerba mate, Ana denanthera, Yohimbe, Kalea, Coffea (Rubiaceae), Sapindaceae, Camellia, Malvaceae, Aquifoliaceae, Hoodia, German chamomile, Passiflora incarnate, Tea plant, Peppermint, Spearmint, European raspberry, Eucalyptus, Lavender, Tachija Kousou, lemon balm, aloe vera, angelica, anise, ayahuasca (banisteriopsis carpi), barley, black mint, blue lotus, burdock, chamomile, caraway, cat's claw, clove, comfrey, corn silk, ryegrass, damiana, damiana, dandelion, ephedra, eucalyptus, evening primrose, fennel, feverfew, fringe tree, garlic, ginger, ginkgo, ginseng, goldenrod, hydrastis, sedge, green tea, guarana, hawthorn, hops, horsetail, hyssop, cola nut,Selected from the group consisting of kraton, lavender, lemon balm, licorice, lion's tail (wild daga), maca bulb, red hollyhock, meadowsweet, milk thistle, motherwort, passionflower, passionflower, peppermint, thistle poppy, purslane, raspberry leaf, poppy, sage, saw palmetto, dwarf yam, cinnamon (Maya sunopener), spearmint, sweet flag, Syrian rue (Peganum harmara), thyme, turmeric, valerian, wild yam, wormwood, yarrow, mate, yohimbe, and any part or combination thereof.

[0178] According to some embodiments of any of the embodiments described herein (methods, apparatus, circuits, or systems), the plant is selected from the group consisting of Cannabis sativa, Cannabis indica, and Cannabis ruderalis.

[0179] According to some embodiments of any of the embodiments described herein (methods, apparatus, circuits, or systems), the pharmacologically active agent is Δ 9 - Selected from the group consisting of tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), cannabinodiol (CBDL), cannabicyclol (CBL), cannabiersoin (CBE), cannabidivarin (CBDV), tetrahydrocannabivarin (THCV), and cannabitriol (CBT).

[0180] According to some embodiments of any of the embodiments described herein (methods, apparatus, circuits, or systems), the pharmacologically active agent is Δ 9 - Selected from the group consisting of tetrahydrocannabinol (THC) and cannabidiol (CBD).

[0181] According to some embodiments of any of the embodiments described herein, any of the methods, apparatus, circuits, or systems described herein are intended for use in treating a medical condition of a subject requiring such treatment.

[0182] According to some embodiments of any of the embodiments described herein (methods, apparatus, circuits, or systems), a medical condition or associated symptoms are improved by pulmonary delivery of at least one pharmaceutically active agent.

[0183] Unless otherwise specified, all technical terms and / or scientific names used herein have the same meaning as those generally understood by a person skilled in the art relating to this disclosure. Similar or equivalent methods and materials described herein may be used in the implementation or testing of embodiments of this disclosure, but some methods and / or materials are described below. In the event of any dispute, this specification, including definitions, shall prevail. Furthermore, materials, methods and examples are illustrative and not necessarily intended to be limiting.

[0184] This patent or attached file includes at least one drawing created in color.

[0185] Some embodiments of the present invention are described herein merely as examples with reference to the accompanying drawings. It should be emphasized here that the details shown are illustrative and are intended for explanatory purposes regarding embodiments of the present invention. In this regard, the description made with reference to the drawings will be clear to those skilled in the art as to how embodiments of the present invention may be carried out. [Brief explanation of the drawing]

[0186] [Figure 1] This is a photograph of a quantitative inhalation device (Syqe Inhaler Exo®) according to some embodiments of the present disclosure (background art). [Figure 2]This is a comparative plot showing Δ9-THC plasma levels after a single inhalation of 15.1±0.1 mg of crushed cannabis flower containing 3.08±0.02 mg of Δ9-THC using a quantitative inhalation device according to some embodiments of the present disclosure. [Figure 3] This graph shows the visual analog scale (VAS) pain intensity after a single inhalation of 15.1±0.1 mg of crushed cannabis flowers containing 3.08±0.02 mg of Δ9-THC. [Figure 4] This graph shows blood pressure and heart rate after a single inhalation of 15.1±0.1 mg of crushed cannabis flowers containing 3.08±0.02 mg of Δ9-THC. [Figure 5] This graph shows the satisfaction score of inhaling crushed cannabis flowers compared to inhaling cannabis flowers for smoking. [Figure 6] This bar graph shows the mean and 95% confidence interval of plasma Cmax levels per 1 mg of Δ9-THC administered by intravenous, vaporization, and smoking-type delivery (see background art and Example 2 below), compared to Δ9-THC plasma Cmax obtained by inhalation using devices according to some embodiments of this disclosure. The numbers in parentheses are the relevant references shown in Example 2 below. [Figure 7] This bar graph shows the inter-individual variability (coefficient of variation, CV(%)) of Δ9-THC plasma Cmax obtained by vaporization, smoking, oral and transoral mucosal delivery (see background art and Example 2 below) compared with Δ9-THC plasma Cmax obtained by inhalation using devices according to some embodiments of this disclosure. The numbers in parentheses are the relevant references shown in Example 2 below. [Figure 8] This is a typical example of lung delivery of three predetermined vaporization amounts (calculated drug doses) over a 3-hour period for patient X. [Figure 9] This is a schematic diagram of a system comprising an inhalation device, a physician interface and / or a patient interface according to some embodiments of the present disclosure. [Figure 10] This is a flowchart illustrating a method for prescribing a personalized regimen to a patient according to some embodiments of the present disclosure. [Figure 11A]This is a schematic diagram of a physician interface for selecting and prescribing a regimen to a patient, according to some embodiments of the present disclosure. [Figure 11B] This is a screenshot of a physician interface for selecting and prescribing a regimen to a patient, according to some embodiments of the present disclosure. [Figure 11C] This is a screenshot of a physician interface for selecting and prescribing a regimen to a patient, according to some embodiments of the present disclosure. [Figure 11D] This is a screenshot of a physician interface for selecting and prescribing a regimen to a patient, according to some embodiments of the present disclosure. [Figure 12] This is a flowchart of a method for obtaining individual pharmacodynamic (PD) parameters from a patient and modifying the regimen accordingly, according to some embodiments of the present disclosure. [Figure 13A] This is a screenshot of a patient interface according to some embodiments of the present disclosure. [Figure 13B] This is a graphical representation of the predicted pharmacodynamic and pharmacokinetic profiles of a patient before and after obtaining an individual PD effect, according to some embodiments of the present disclosure. [Figure 13C] This is a screenshot of a patient interface according to some embodiments of the present disclosure. [Figure 13D] This is a graphical representation of the predicted pharmacodynamic and pharmacokinetic profiles of a patient before and after obtaining an individual PD effect, according to some embodiments of the present disclosure. [Figure 13E] This is a screenshot of a patient interface according to some embodiments of the present disclosure. [Figure 14] This is a flowchart of a method for acquiring one or more biomarkers using a personal portable device and / or inhalation device, according to some embodiments of the present disclosure, and for partially modifying the dose and / or regimen as necessary. [Figure 15A-15C]A print screen of a patient interface, according to some embodiments of the present disclosure, comprising various applications for obtaining biomarkers and / or assisting patients in determining perceived therapeutic and / or adverse effects. [Figure 16] This is a schematic diagram of a quantitative inhalation device configured to automate and control the delivery of one or more active drugs to the lungs, according to some embodiments of the present disclosure. [Figure 17A] This is a schematic diagram of the configuration of an inhalation device according to some embodiments of the present disclosure. [Figure 17B] A cartridge for an inhalation device, which, according to some embodiments of this disclosure, is synonymous with “dose unit” or “dose cartridge” in this specification and which contains individual doses as needed. [Figure 17C] Other freely selectable shapes of the cartridge according to some embodiments of this disclosure. [Figure 17D] Other freely selectable shapes of the cartridge according to some embodiments of this disclosure. [Figure 18] This is a flowchart of a method for treating individual patients using a system according to Figure 9, while maintaining the patient within a personalized treatment window, according to some embodiments of the present disclosure. [Figure 19] This is a flowchart of the procedure for determining and administering individual medication dosages and / or regimens to treat neurological pain in human subjects. [Figure 20] This is a graphical representation of a regimen for treating pain and insomnia through pulmonary delivery of an active drug. The red line represents the pain level, and the green line represents the blood level of the active drug. The active drug has analgesic and sedative effects. [Figure 21]This graph shows a regimen for pain treatment using pulmonary delivery of a combination of two active drugs, THC and CBD. The dashed line represents the level of adverse (psychoactive) effects, and the solid line represents the pain level. THC is inhaled using dose units of 0.5 mg (white triangle), 1.2 mg (gray triangle), and 2.4 mg (black triangle), while CBD is inhaled using a dose unit of 25 mg (white diamond). [Modes for carrying out the invention]

[0187] The present invention relates to pharmacology in some embodiments, but more specifically, to methods, apparatus and systems for controlled pulmonary delivery of active drugs, without limitation.

[0188] Before describing in detail at least one embodiment of the present invention, it should be noted that, naturally, the present invention is not necessarily limited in its application to the details described below or illustrated in the examples.

[0189] As previously mentioned, the difficulty in controlling the delivery of naturally derived pharmaceutical active agents, according to accepted pharmacological practices, limits the medicinal uses of several clinically evaluated natural substances, such as active substances found in plants and herbs, the most prominent example being cannabis. The inability to determine and control accurate and precise dosages is one of the main obstacles when adding natural substances, which play a major role in the medicamentotherapy regimens available for the treatment of many medical conditions. Furthermore, without standardized and approved pharmaceutical protocols for the administration of naturally derived active agents, it is impossible for physicians to prescribe treatments according to those protocols.

[0190] Standard pharmacological rules stipulate that the treatment of medical conditions using pharmacologically active drugs must be based on therapeutically effective doses administered according to therapeutically effective regimens, while striving to maintain a balance between therapeutic and adverse effects.

[0191] Furthermore, as mentioned above, Patent Document 1 discloses a metered-dose inhalation (MDI) device capable of accurately and consistently delivering plant-derived active agents such as cannabis-derived cannabinoids. Figure 1 is a representative example of such an inhalation device. While conceiving this disclosure, it is presumed that such MDI devices would bridge the gap between the use of natural substances containing promising pharmaceutical active agents and the standard, rigorous pharmacological regulations for the use of any pharmaceutical active agent in treating any medical condition.

[0192] In implementing the present invention, the inventors conducted pharmacokinetic ("PK") and pharmacodynamic ("PD") studies ("PK / PD studies") of pulmonary delivery (inhalation) of cannabis-derived cannabinoids to human subjects in accordance with well-established pharmacological protocols, demonstrating that at least one cannabis-derived cannabinoid can be administered using an accurate and precise MDI device. Furthermore, this study demonstrated that the MDI device used in the present invention is more effective and efficient than other known methods and devices known in the art for the accurate and reproducible release of vaporized cannabis-derived pharmaceutically active agents (one or more). As used herein, the terms "pharmacokinetic / pharmacodynamic" and "PK / PD" mean pharmacokinetic and / or pharmacodynamic.

[0193] The results of this study pave the way for the pulmonary delivery of a wide range of natural plant materials using the precision MDI device described above, under widely accepted pharmaceutical and regulatory conditions. Such pulmonary delivery may be used to treat a wide range of medical conditions in which volatile agents in the natural plant materials are beneficial for the treatment of a medical condition and / or the improvement of symptoms of a pathological condition.

[0194] This PK / PD study demonstrates that analytical means can be provided for determining and personalizing therapeutically effective doses and / or regimens to treat neurological pain in human subjects. Such doses and / or regimens can maintain treatment within the therapeutic window limits of THC in human subjects, i.e., the doses and / or regimens can provide accurate and / or reproducible pharmacokinetic profiles that provide pre-selection of THC or a predetermined pharmacokinetic profile in subjects requiring it.

[0195] As used herein, the terms “therapeutic window” and “pharmaceutical window” are synonymous and refer to the range of pharmacodynamic effects induced by the dose range of one or more pharmacoactive agents, thereby maintaining a balance between one or more desirable (positive) effects and one or more adverse (negative) effects. According to some embodiments, the pharmacodynamic / therapeutic window is referred to as the pharmacodynamic profile. The window may be associated with a given point in time, or within a range of any length, such as minutes, hours, days, or longer periods, shorter periods, or any intermediate period. The degree of desirability of an effect can be determined based on a variety of criteria, including, but not limited to, medical practice, rules and regulations, cultural and demographic levels, genetic factors and personal preferences, and tolerance. For example, the degree of desirability of an effect can be determined based on the purpose of treatment and generally acceptable values, and other parameters such as patient preferences, abilities, and activities may be taken into consideration as needed. It should be noted that a certain effect may be considered desirable in some cases, but undesirable in others, and vice versa.

[0196] According to some embodiments of the present invention, methods, apparatuses and systems provided herein are capable of vaporizing a predetermined vaporization amount of an active agent in a given subject or population of subjects to induce one or more predetermined pharmacodynamic effects, wherein the predetermined pharmacodynamic effect is related to a predetermined pharmacodynamic profile that can vary between a minimum level of desirable effect and an arbitrary level of undesirable effect.

[0197] In some embodiments, this pharmacokinetic window ranges from the lowest level of effective treatment of a medical condition (therapeutic effect; e.g., pain relief) to the highest level of tolerable adverse effect (e.g., tolerable psychoactive effects as described herein). If necessary, the treatment window may correlate with a selected balance between therapeutic and adverse effects. For example, undesirable effects may be sufficiently tolerable or even minimized, while desirable effects reach at least a minimum acceptable or minimum essential level (e.g., saving the user's life, or preserving the function of an organ or tissue). If necessary, adverse effects may be limited depending on the subject's preferences or the likelihood of serious or irreversible harm to their health. However, several alternative balances are possible, and effects may be selected between selective treatment windows based on the user's preferences.

[0198] Throughout this specification, the term “patient” is used interchangeably with the terms “subject,” “user,” and “individual requiring it,” to refer to an entity that is a subject using any of the devices and systems provided herein and being subjected to any of the methods provided herein.

[0199] The therapeutic window can be correlated with a range of amounts of one or more pharmaceutically active agents via a pharmacokinetic profile. For example, the therapeutic window may be defined as a range of amounts of one or more pharmaceutically active agents that extends from an amount that confers a desired effect (a therapeutic effect, in this case, the amount being a therapeutically effective amount or a therapeutic dose) to an amount that exceeds an acceptable or tolerable level of an undesired effect (e.g., a harmful effect). Thus, for example, pharmaceutically active agents with a narrow therapeutic window need to be administered and controlled with great care to stay between the therapeutically effective amount and the amount that causes a harmful effect.

[0200] The therapeutic index can be expressed in terms of the therapeutic ratio (TR), which is the ratio of the toxic dose (TD) or lethal dose (LD) to the effective dose (ED). The higher the TR, the safer the drug. For example, the therapeutic index of tetrahydrocannabinol (THC) is 1000 and is thus considered a safe active agent, while the therapeutic index of digoxin, a cardiac glycoside, is approximately 2:1, which means that a high level of drug monitoring is required for the drug. Thus, in some embodiments, the therapeutic window is affected by the therapeutic index of one or more pharmaceutically active agents and combinations thereof.

[0201] According to one aspect of some embodiments of the present disclosure, there is provided a method of pulmonary delivery of at least one pharmacologically active agent to a patient, which is carried out by using a metered inhalation device to deliver the agent to the patient's lungs, the device being configured to release at least one predetermined vaporization amount of the agent when a substance containing the agent is controllably heated, the amount being set to achieve at least one predetermined effect in a subject such as a predetermined pharmacodynamic effect.

[0202] According to one aspect of several embodiments of the present disclosure, a method is provided for vaporizing at least one pharmacologically active agent present in a plant material and suitable for pulmonary delivery to a patient, the method being performed using a metered-dose inhalation device, the device configured to release a predetermined vaporized amount of at least one agent when the plant material is controlledly heated, the amount being set such that at least one predetermined pharmacokinetic effect and / or at least one predetermined pharmacodynamic effect is achieved in a subject by the agent upon pulmonary delivery to a patient.

[0203] According to one aspect of several embodiments of the present disclosure, the use of a metered-dose inhalation device is provided for vaporizing at least one pharmacologically active agent present in a plant material suitable for pulmonary delivery to a patient, the device being configured to release a predetermined vaporized amount of at least one agent when the plant material is controlledly heated, the amount being set such that, upon pulmonary delivery of the agent to a patient, at least one predetermined pharmacokinetic effect and / or at least one predetermined pharmacodynamic effect is achieved in the subject.

[0204] Naturally, the pharmaceutically active agent can be in solid or liquid form; it should be further noted that the agent is contained in the solid substance described herein. According to some embodiments of this disclosure, the pharmaceutically active agent is vaporizable by heat and thereby released from the substance by thermally induced vaporization.

[0205] According to some embodiments, the substance containing at least one volatile active agent is, for example, a plant material. In some embodiments, the active agent is a naturally occurring agent, i.e., the agent occurs naturally in plants. Alternatively, the substance may contain, for example, one or more natural plant materials, or be an organic material consisting solely of natural plant materials, or a synthetic material that may contain at least one volatile active agent. In some embodiments, the solid substance contains multiple volatile active agents derived or extracted from natural or organic raw materials such as plants, fungi, or bacteria.

[0206] In some embodiments, the substance is a natural plant material. In one embodiment of this disclosure, the plant material is treated without damaging the volatile active agents within the plant material. If necessary, the plant material retains its macroscopic plant structure.

[0207] The amount of substance used in the MDI device may be determined based on the content of the volatile agent contained therein and the predetermined vaporization amount required to be released from the device. The amount of substance used in the MDI device may be in the range of 20-500 mg, 10-200 mg, 9-150 mg, 8-100 mg, 7-50 mg, 5-20 mg, 1-10 mg, 10-70 mg, 10-60 mg, 12-50 mg, 12-40 mg, 15-40 mg, 12-30 mg, or 12-25 mg.

[0208] The terms “pharmaceutically active agent,” “biologically active agent,” “active agent,” and “agent” are used interchangeably herein and refer to a compound, polymer, complex, or any combination thereof that exhibits a physiological or psychological effect when administered to a subject. Typically, pharmaceutically active agents or biologically active substances exert their desired physiological or psychological effect when delivered to a target organ via systemic pathways (e.g., blood, lymph). Agents may be naturally derived or synthetic. Non-limiting examples of active agents include CNS activators, chemotherapeutic agents, sedatives or analgesics, and psychotropic agents. In the context of the embodiments of this disclosure, a pharmaceutically active agent is a naturally occurring agent found in a naturally occurring substance (e.g., a natural plant substance as described herein) or its metabolites. Unless otherwise indicated, these terms also encompass two or more agents.

[0209] According to some embodiments of the present disclosure, the method is carried out using a medium-dose inductive (MDI) capable of reproducibly and accurately delivering a certain amount of at least one volatile agent by heating a solid substance. The requirements of such an MDI can be met by MDIs such as those disclosed in Patent Document 11 or Patent Document 1, both of which are incorporated herein by reference in their entirety to the extent fully presented herein.

[0210] According to some embodiments of this disclosure, the MDI apparatus is the apparatus described in Patent Document 1, which includes any one of the embodiments described in said document and any combination thereof.

[0211] As used herein, the term "vaporized amount" refers to the amount of agent in vapor form, while vapor form / amount is obtained using a heating element in the MDI device. Note that in some embodiments herein, the vaporized agent amount in the context of this disclosure represents the actual amount evaporated by the heating, rather than an estimated amount.

[0212] The term “prescribed vaporization volume” refers to the amount intentionally or deliberately released from the MDI device, the scale of which is determined by the selection or design of the dose and / or regimen protocol as described herein. In the context of some embodiments, the term “dose” refers to the prescribed vaporization volume. It should be noted that the prescribed vaporization volume correlates with the available amount present in the device, and that the prescribed vaporization volume can be pre-set, reset, adjust, and / or readjusted accordingly by pre-measuring the available amount present in the device or by measuring the available amount present in the device in conjunction with the administration event.

[0213] Initial dose determination and device calibration: According to some embodiments, a method is employed to select / control a predetermined vaporization rate such that a pre-selected (also referred to herein as “predetermined”) pharmacokinetic profile and / or a pre-selected or predetermined pharmacodynamic profile of the drug is observed in the patient.

[0214] In some embodiments, a predetermined vaporization volume is arbitrarily selected / determined, and the MDI device is configured to vaporize and deliver this volume consistently and accurately after any number of uses and inhalations using any raw material (substance: plant material, combination of plant material and other materials, etc.) of the active agent. According to some embodiments, the predetermined vaporization volume of the agent can be determined based on a measurement of the amount of agent per unit mass of the substance from which the agent is vaporized. Such measurements can be performed using standard procedures; thereby, it is possible to standardize various batches of substances and raw materials according to the relative amount of agent per unit mass of the substance.

[0215] It should be noted that, according to some embodiments of this disclosure, the presentation of a pre-selected pharmacokinetic and / or pharmacodynamic profile means that the amount of vaporized drug has been predetermined based on a pharmacokinetic / pharmacodynamic (PK / PD) test performed on at least one subject by delivering the drug to the lungs using an MDI device configured to release a constant and precise amount of vaporized drug when a solid substance containing the drug is heated. It should also be noted that, according to some embodiments of this disclosure, the presentation of a pre-selected pharmacokinetic profile means that at least one desirable pharmacokinetic profile has been identified and at least one predetermined vaporized amount of the drug has been shown to be effective for that desirable pharmacokinetic profile in the subject.

[0216] In some embodiments of this disclosure, the terms “pre-selected” and “predetermined” refer to, or are used synonymously with, the terms “intended,” “desired,” or “preferred,” or the terms “effective,” “necessary,” and “therapeutic.”

[0217] It should also be noted that the identification of a desirable pharmacokinetic profile and / or pharmacodynamic profile can usually be performed by conducting PK / PD tests on a specific pharmaceutically active agent in a specific subject or group thereof. Furthermore, it should be noted that the possibility of performing standard and widely approved PK / PD tests on a pharmaceutically active agent delivered by inhalation (pulmonary delivery) in a specific subject or group thereof, when the amount of the agent vaporized by heating a solid sample of a substance is released in a controllable and reproducible manner, can be made possible, for example, by an MDI device such as the one disclosed in Patent Document 1, which can use plant materials as raw materials for the active agent(s).

[0218] In some embodiments, the term “predetermined vaporization volume” is also used herein to describe the amount of drug determined based on pharmacokinetic / pharmacodynamic (PK / PD) data of the drug in one or more patients, i.e., the vaporization volume determined by determining the PK / PD effect (parameter).

[0219] In some embodiments, configuring the MDI device to release a predetermined amount as defined herein means, in some embodiments, calibrating the device to exhibit a pre-selected PK and / or pre-selected PD profile.

[0220] According to any few embodiments of the embodiments of the present disclosure, the method is carried out by adjusting a predetermined vaporization rate to achieve a predetermined pharmacokinetic effect and / or predetermined pharmacodynamic effect based on data showing that the drug induces at least one pharmacokinetic effect and / or at least one pharmacodynamic effect in a subject.

[0221] In some embodiments, the method further includes the step of generating index data by monitoring at least one pharmacokinetic effect and / or at least one pharmacodynamic effect induced by the drug in a subject.

[0222] According to some embodiments of any of the embodiments of the present disclosure, the method is carried out by monitoring and / or determining at least one pharmacokinetic effect and / or at least one pharmacokinetic variable factor and / or at least one pharmacodynamic effect, as the terms are defined herein, these effects and variable factors being the pulmonary delivery of a pharmaceutically active agent to a patient using an MDI device; determining a predetermined vaporization amount indicative of a preselected pharmacokinetic profile and / or a preselected pharmacodynamic profile of the agent in the patient, based on the pharmacokinetic effect and / or pharmacokinetic variable factor and / or pharmacodynamic effect; and induced by adjusting the MDI device to deliver the predetermined vaporization amount of the agent.

[0223] As used herein, the phrase "pharmacokinetic profile" means the concentration in the body of a pharmaceutically active agent or its metabolite (e.g., an active metabolite), i.e., the concentration of the agent or its metabolite as a function of time in the physiological system of the living body (whole body, blood, plasma, lymph, tissue, organ, etc.) to which the compound has been administered. Usually, the pharmacokinetic (PK) profile is considered from the time of administration of the compound until the time when the compound can no longer be detected in the living body, or for any intermediate period of time between the time of administration of the compound and the time when the compound can no longer be detected in the living body (e.g., for excretion); thus, the PK profile describes the in vivo concentration of a particular compound in a particular physiological system between administration and disappearance, such that it is affected by the mechanisms of liberation, absorption, distribution, metabolism, and excretion / secretion of the compound. Since each living body, and each individual living body within a genus of living bodies, exhibits a different response to drug administration, the PK profiles may be different, may vary considerably between subjects, and may also vary within an individual subject depending on the current physiological state, medical state, environmental state, and even the time of day.

[0224] According to some embodiments of this disclosure, a pharmacokinetic profile is achieved by providing the subject with one or more of the following: Dosage - the single dose of the compound or drug administered to the subject; and / or A regimen is a set of predetermined doses provided at various time intervals, the amounts of which can be different or similar, and the durations of which can be different or similar. In some embodiments, the regimen also includes a delivery period (e.g., drug administration period or treatment period).

[0225] Alternatively, the regimen is a set of predetermined vaporization amounts given at predetermined time intervals.

[0226] It should be noted that the PK profile can be determined according to the changes in the PK effect (parameter) as a function of time, or the combination of PK effects as a function of time.

[0227] PK profiles are typically evaluated as concentrations against a time scale using directly and / or indirectly measured PK effects. For example, a PK profile may be the plasma concentration of an administered pharmaceutically active agent in a subject as a function of time.

[0228] As used herein, the term “pre-selected pharmacokinetic profile” refers to a PK profile selected as desirable. A pre-selected PK profile may be chosen because it has been found to be effective in achieving a desired pharmacokinetic effect in a subject, as described in any one of the embodiments (for example, to maintain the subject within the therapeutic window as described herein).

[0229] In this specification, the terms "pharmacokinetic parameters" and "pharmacokinetic effects," used interchangeably, refer to measurable and quantifiable physiological effects in a subject that relate to the presence of a pharmacokinetic agent in the subject. PK effects are the direct or indirect manifestations of a group of physiological processes in a subject, including the absorption, distribution, metabolism, and excretion (ADME) of a pharmacokinetic agent.

[0230] While not exhaustive, typical PK effects include the following: C t : The concentration of a drug determined, measured, or evaluated in a specific physiological system (e.g., in plasma) after administration (delivery, e.g., pulmonary delivery) to a subject at a certain dose or regimen; C max : The peak concentration of a drug determined, measured, or evaluated in a specific physiological system (usually plasma) after administration to a subject; T max : Administration and C max This is the elapsed time between arrival and departure; Area under the curve (AUC 0→∞ (From zero to infinity), this is typically the integral of the concentration curve as a function of time after a single dose or at a steady state; C min : This is the lowest concentration of the drug in the body before the next administration; T min :C min This is the time elapsed until detection occurs or until the next dose is administered; C last : The final quantifiable concentration observed; λ z , the terminal rate constant; Elimination half-life (t 1 / 2 ): This is the time required for the drug concentration to reach 1 / 2 of an arbitrarily selected value; Ejection rate constant (k E ): The rate at which a drug is removed from the body; Administration rate (k in ): This is the administration rate necessary to maintain balance in excretion; Clearance: The amount of plasma released from a drug per unit time; Bioavailability: The proportion of a drug that can be used systemically. Variability: This refers to the peak-trough variation within a single dose or dosing interval under steady-state conditions.

[0231] As a tool for evaluating PK profiles in a group of similar individual subjects (with a biological meaning similar to a human population), PK variable elements found to correlate with PK profiles in subgroups within that group may be used to generalize (extrapolate) the PK profiles of each individual, including the entire group.

[0232] As used herein, the term "pharmacokinetic variable" refers to a subject characteristic that is not necessarily dependent on the pharmacokinetic agent or the method of delivering the pharmacokinetic agent to the subject, and provides information related to the factors that influence the pharmacokinetic and pharmacodynamic profiles of the pharmacokinetic agent in the subject.

[0233] Pharmacokinetic variables typically include, but are not limited to, body weight, height, body mass index (BMI), waist-to-hip ratio, lean body mass (LBM), age and sex, race, underlying medical conditions, patient history (e.g., past exposure to the drug in question or other drugs), and concomitant medications. Naturally, PK variables depend on the genetic and epigenetic composition of each individual subject and can therefore be used to predict the PK / PD profile of each individual with a certain degree of accuracy. However, personalization of treatment based on the administration of pharmacokinetic agents is usually based on obtaining individual PK / PD effect / parameter data to use in determining the dose and regimen for each individual subject. Generally, the deviation of individual parameters from mean parameters set in a broad population is remarkably small.

[0234] In the context of some embodiments of this disclosure, the term “treatment” means: a single pulmonary administration of a given dose of a drug; a fixation and limited series of pulmonary administrations of the drug at the same or different doses at the same or different dosing intervals (regimens); a limited series of administrations without a planned termination of treatment (sequential treatment); and / or any combination thereof. Typically, a series of predetermined doses administered at predetermined intervals is referred to herein as a treatment regimen or regimen.

[0235] According to some embodiments of the methods presented herein, pulmonary delivery of a drug may include a single dose delivered as a predetermined vaporization volume released by an MDI device in a single inhalation session, or a dose that may be administered to the patient as several combined inhalations. Alternatively, a series of doses, each administered at one or more predetermined vaporization volumes and at predetermined time intervals, is referred to herein as a regimen. Thus, a regimen is defined by one or more doses administered at one or more predetermined vaporization volumes at predetermined time intervals, where the predetermined vaporization volume, dose, and time interval may be the same or different.

[0236] In the context of embodiments of this disclosure, the PK profile of a given pharmaceutically active agent is the result of a dose and / or regimen that enables the agent to be administered to a patient, or, according to some embodiments, the PK profile is an average value to provide a specific pre-selected pharmacodynamic profile of the agent in a patient, or otherwise a desirable pharmacodynamic profile.

[0237] As used herein, the term “pharmacodynamic profile” refers to the effect of a pharmacokinetic agent in a subject as a function of time. Therefore, the term “pharmacodynamic profile” refers to the sum of all biological expressions and responses in a living organism as a function of time after administration of a pharmacokinetic agent. A pharmacodynamic profile is typically the pharmacokinetic effect(s) at any given point in time, or the direct or indirect result of the pharmacokinetic profile of a drug in a patient over any given period of time.

[0238] A pharmacodynamic profile is the change / variation of pharmacodynamic effects (one or more) directly and / or indirectly determined as a function of time.

[0239] In this specification, the terms "pharmacodynamic parameters" and "pharmacodynamic effects," used interchangeably, refer to a group of effects related to the subject and the pharmacodynamic agent, which appear in the subject when the agent is administered. Typically, pharmacodynamic parameters depend on the subject's PK variable elements and the subject's PK effects.

[0240] Pharmacodynamic parameters can typically be determined by determining the level of biomarkers (indicating therapeutic and / or adverse effects) by therapeutic (desired) effects (e.g., therapeutic effects perceived by an individual) and adverse (undesired) effects (e.g., adverse effects perceived by an individual), as these terms are described below. A pharmacodynamic profile that may be a pre-selected (desired) pharmacodynamic profile according to some embodiments of this disclosure is determined by the therapeutic window of a given drug in a given subject, as the terms are defined herein.

[0241] A pharmacodynamic (PD) profile is typically a time-dependent assessment and / or measurement of a scale that begins with no response, progresses through the onset of a desirable therapeutic effect (below the therapeutic effect threshold), crosses the therapeutic window, progresses through the onset of an adverse effect (above the adverse effect threshold), and reaches a toxic effect.

[0242] According to some embodiments of this disclosure, lung delivery and / or PK / PD studies (measurement of any pharmacokinetic and / or pharmacodynamic parameters) are performed while monitoring, if necessary, at least one additional physiological parameter selected from the group consisting of: Vital signs selected from the group consisting of heart rate, oxygenation level (SpO2), blood pressure, respiratory rate, and body temperature; Lung function selected from the group consisting of forced expiratory capacity (FEV1), maximum intermediate expiratory flow rate (MMEF), carbon monoxide pulmonary diffusion capacity (DLCO), forced vital capacity (FVC), total lung volume (TLC), and residual lung volume (RV); Hematological markers selected from the group consisting of hemoglobin level, hematocrit ratio, red blood cell count, white blood cell count, white blood cell differential, and platelet count; Coagulation parameters selected from the group consisting of prothrombin time (PT), prothrombin ratio (PR), and international normalized ratio (INR); Renal function markers selected from the group consisting of creatinine clearance (CCr), blood urea nitrogen level (BUN), and glomerular filtration rate (GFR); and A liver function marker selected from the group consisting of aspartate aminotransferase (AST) levels, serum glutamate oxaloacetate transaminase (SGOT) levels, alkaline phosphatase levels, and gamma glutamyltransferase (GGT) levels.

[0243] Therefore, the results of such PK / PD studies conducted on one or more subjects can be used to determine the initial predetermined vaporization volume of at least one pharmacologically active agent that exhibits an initial pre-selective pharmacokinetic and / or initial pre-selective pharmacodynamic profile in a particular patient when administered by an MDI device configured for lung delivery. Furthermore, these results can be used to calibrate and pre-configure similar MDI devices to deliver the initial predetermined vaporization volume and achieve similar consistent initial results.

[0244] By considering one or more specific criteria and variable factors as necessary, such as age and weight, the PD effect and profile can also be determined or estimated based on statistical data relating to a population, as the term is described herein in the context of PK effects, based on approximations that allow us to predict the PD effect of a drug in another subject by considering the PD effect induced by a given active drug in one subject.

[0245] As described herein, if an inhalation device is accurate and consistent in vaporizing and delivering at least one active agent in a predetermined vaporization volume, it becomes possible to perform PK / PD testing on one or more subjects using that device. Such testing is based on the ability to accurately and consistently record the PK / PD effect.

[0246] Accordingly, a method is provided for recording at least one pharmacokinetic effect and / or at least one pharmacodynamic effect induced by delivering at least one pharmacologically active agent present in a plant material to a subject via lung delivery; the method is; Delivering a predetermined amount of a drug to a subject's lungs from a quantitative inhalation device configured to vaporize a predetermined amount of the drug when a plant-based material is heated in a controllable manner; If necessary, determine at least one pharmacokinetic effect in the subject before, during, and / or after pulmonary delivery at predetermined time intervals; This is carried out by determining at least one pharmacodynamic effect in the subject at predetermined time intervals before, during, and / or after lung delivery; Pharmacodynamic effects are selected from a group consisting of desirable effects, undesirable effects, therapeutic effects, adverse effects, and biomarker levels.

[0247] Personalization: As previously mentioned, some PK / PD studies, or parts thereof, are based on population parameters and cohorts that generate mean or standardized dose and / or regimen data, whereas in reality, PK / PD profiles are diverse among patients and even within individual patients, depending on their current physiological, mental, medical, and environmental conditions. Therefore, for a particular individual at a given time, and for individual reasons, a predetermined vaporization volume of the drug (pre-set dose and / or regimen) may be considered insufficient. Accordingly, in order to provide treatment optimized for a given individual in any of the methods presented herein, each of the pharmacokinetic and / or pharmacodynamic parameters and / or variable elements may be further determined for individual patients, thereby individually inducing a predetermined vaporization volume for each patient.

[0248] According to some embodiments of the present disclosure, the patient may initiate lung delivery using an initial predetermined vaporization volume that is not determined based on the patient's personal / individual parameters and variable factors, but it should be noted that such methods also include a selective step in which the patient's personal parameters and variable factors are taken into consideration in determining the predetermined vaporization volume. Accordingly, according to some embodiments of the embodiments of the present disclosure, such methods may include personalization of the predetermined vaporization volume to provide a pre-selected PK / PD profile. The personalization step presented below can replace the pre-calibration of the MDI device; or it can be performed as a complementary step after the calibration of the MDI device.

[0249] Therefore, the pharmacokinetic effects (one or more) and / or pharmacokinetic variable factors (one or more) and / or pharmacodynamic effects (one or more) are determined separately for each individual patient, thereby determining the predetermined vaporization volume individually for that patient. It should be noted herein that an individual's pharmacokinetic parameters can be directly obtained by monitoring the patient's drug concentration (e.g., using blood samples and / or other means) and performing a PK test in the patient, or by applying calculations based on the patient's individual PK variable factors and other individual variable factors that may affect the PK / PD profile.

[0250] Alternatively, according to some embodiments of the embodiments of the present disclosure, in order to determine whether the initial vaporization of a predetermined amount of drug delivered to the lungs exhibits a pre-selected (desired) pharmacodynamic and / or pharmacokinetic profile, the method includes the step of collecting, observing, or monitoring and determining at least one individual pharmacodynamic and / or pharmacokinetic effect in each subject; If the lung delivery of a predetermined vaporized amount of drug does not exhibit a pre-selected / predetermined pharmacodynamic and / or pharmacokinetic profile, the step of determining an adjusted vaporized amount of drug that exhibits a pre-selected pharmacodynamic and / or pharmacokinetic profile; The process includes adjusting, resetting, recalibrating, or reconfiguring the device to deliver the adjusted vaporization amount, thereby ensuring that when the MDI device is reconfigured, the adjusted vaporization amount is a predetermined vaporization amount at that point.

[0251] According to some embodiments of this disclosure, personalization of the lung delivery and / or PK / PD study may be optionally performed while monitoring at least one additional physiological parameter as described herein. If necessary, monitoring of at least one pharmacokinetic and / or pharmacodynamic effect induced by the drug in the subject is performed at predetermined time intervals before, during, and / or after lung delivery.

[0252] According to some embodiments, monitoring of pharmacokinetic and / or pharmacodynamic effects is performed by receiving data indicating these effects in a subject from at least one sensor communicating with a controller associated with the inhalation device presented herein, as these terms are described below.

[0253] It should be noted that an individual's pharmacodynamic parameters may include the therapeutic effect perceived by the individual, the adverse effect perceived by the individual, and biomarkers (levels or presence) obtained and / or measured in individual patients. According to some embodiments, the acquisition / determination of the therapeutic effect perceived by the individual, the adverse effect perceived by the individual, and / or biomarkers may be performed voluntarily or unconsciously by automated means by the patient. According to some embodiments, this method is performed by then determining an adjusted vaporization amount of the drug based on the individual's pharmacodynamic parameters and configuring the device to deliver the adjusted vaporization amount; thereby the adjusted vaporization amount becomes a predetermined vaporization amount. In other words, the adjusted vaporization amount is a personalized predetermined vaporization amount based on the individual's pharmacodynamic parameters obtained in individual patients after administration of a predetermined vaporization amount determined for the general population using population PK variable elements. Alternatively, the expected response can be used as a parameter to verify the user's personal identification information. For example, the user is instructed to perform tasks at given times before and / or after administration, and the measured values ​​are, in some cases, compared to comparable expected values ​​recorded for the same user under similar circumstances.

[0254] Effects perceived by individuals: "Perceived effects" refer to a patient's subjective assessment of the effects of a drug or treatment administered to their body. Perceived effects may include one or more of the therapeutic or adverse effects perceived by the individual.

[0255] Psychoactive effects may, in some cases, correspond to symptoms that the patient can perceive. It should be noted that psychoactive effects may not always be accurately perceived by the patient. Examples of psychoactive symptoms include, but are not limited to, paranoia, anxiety, panic attacks, euphoria, pseudo-hallucinations, sedation, altered conscious perception, cheerfulness, metacognition and introspection, facilitated recollection (episodic memory), amnesia, sensual changes, altered sensory awareness and libido, dizziness, ataxia, euphoria, altered perception, temporal distortion, intensification of normal sensory experiences, short-term memory, attention, response impairment, proficiency activity, speech fluency, addiction, depression, and depression.

[0256] Physical effects may correspond to symptoms that the patient can perceive or evaluate. Examples of physical symptoms include, but are not limited to, pain, migraine, nausea, dry mouth, coldness or warmth of the hands and feet, increased heart rate, increased cerebral blood flow (e.g., migraine symptoms, "head pressure"), bronchodilation (cough and difficulty breathing), vasodilation (e.g., tremors, skin redness, flushing), conjunctival congestion and pupil dilation, dry mouth, thirst, hunger or craving for food.

[0257] Desired effect - therapeutic effect: "Personally perceived therapeutic effect" is a patient's subjective assessment of the beneficial (desired) effect of a drug administered to the patient's body. In some embodiments, desirable effects include symptom relief and / or reduction of the cause of a medical condition. For example, if a desirable therapeutic effect is defined as pain relief, the patient may report their pain level using a pain scale assessment protocol. The pain scale protocol measures the patient's pain intensity and / or other characteristics. In the context of the embodiments of this disclosure, the pain scale protocol is based on self-reported (subjective), observational, and / or behavioral data provided by the patient, while physiological data constitutes a definition of a biomarker, i.e., objective data. Generally, all personally perceived (subjective) assessments by the patient can be used as feedback for self-titration and personalization of treatment.

[0258] The therapeutic effect perceived by an individual may be directly or indirectly related to, or equivalent to, the symptoms of the medical condition being treated. In some cases, a patient may perceive a change in the perceived level of symptoms, and when the symptoms of the medical condition are alleviated (a decrease in symptom level), the patient may attribute this change to the therapeutic effect of the medication delivered during treatment. Accordingly, according to the embodiments, the therapeutic effect perceived by an individual may correspond to, but is not limited to, a decrease in the level of symptoms such as pain, migraine, depression, cognitive impairment, attention deficit, hyperactivity, anxiety disorders, diarrhea, nausea, vomiting, insomnia, delirium, changes in appetite, sexual dysfunction, spasticity, increased intraocular pressure, bladder dysfunction, tics, Tourette's syndrome, post-traumatic stress disorder (PTSD) symptoms, inflammatory bowel disease (IBD) symptoms, irritable bowel syndrome (IBS) symptoms, excessive tension, bleeding symptoms, sepsis and cardiogenic shock, drug dependence and cravings, withdrawal symptoms, tremors, and other motor dysfunction symptoms.

[0259] In some embodiments, the therapeutic effect perceived by an individual may include effects that are beneficial to symptoms experienced by the patient, even though they are not directly or indirectly related to, or equivalent to, the symptoms of the medical condition the patient is being treated for. For example, when symptoms include the form of discomfort (e.g., pain or nausea), the patient may benefit from a psychoactive state in which the discomfort may be less noticeable or more tolerable. One example of such a desirable effect is the temporary, moderate numbness that occurs during pain. In some embodiments, depending on the degree and / or timing and / or other circumstances, the same effect may be therapeutic or harmful.

[0260] Undesirable effects - harmful effects: "Individual-perceived adverse effects" are caused directly or indirectly by the pharmacokinetic parameters of the pharmaceutical active agent delivered to the patient, and therefore involve the appearance and / or elevation of undesirable symptoms that are not necessarily related to the medical condition being treated.

[0261] According to some embodiments, the undesirable effects perceived by an individual may be mental effects, psychoactive effects, and / or physical effects, where mental and / or psychoactive effects are primarily related to CNS activity encompassing perceptual, conscious, cognitive, and behavioral effects, and physical effects are related to all other bodily systems, including but not limited to gastrointestinal, neuromuscular, cardiovascular, convulsive, and endocrine effects.

[0262] Individual-perceived adverse effects are the patient's subjective assessment of the adverse effects of the administered drug while it is in the patient's body. Generally, all patient assessments of individual-perceived (subjective) adverse effects can be used as feedback for the personalization and self-titration of treatment.

[0263] Biomarkers: Perception of effect is a subjective assessment of effect, and is usually complex to quantify, whereas biomarkers are more objective and are usually measurable quantitative assessments of effect. Therefore, as used herein, the term “biomarker” refers to a measurable indicator of the PD profile at a given point in time, and typically consists of direct and / or indirect physical, biological, and / or chemical manifestations of therapeutic and / or adverse effects. In other words, a biomarker may be any objectively measurable quantity that can be used as an indicator of the state of a medical condition, the effect of a particular drug on the state of a medical condition, or another physiological state of the organism. It should be noted that some therapeutic / adverse effects can only be assessed qualitatively, while others can be assessed indirectly, for example, by applying performance tests to measure the impaired response.

[0264] In the context of the embodiments of this disclosure, biomarkers are divided into groups of invasively detectable biomarkers and non-invasively detectable biomarkers. Generally, all (objective) biomarker data collected in patients by any average measurement, sensor measurement, etc., can be used as feedback for the personalization of treatment and self-titration. Note that some invasively detectable biomarkers can be detected and measured non-invasively, and vice versa.

[0265] Examples of non-invasively detectable biomarkers include heart rate, oxygenation level (SpO2), blood pressure, respiratory rate, body temperature, inhalation volume, facial expression, involuntary movements, skeletal muscle responses (ataxia, tremors, muscle contractions, spasms, etc.), voluntary motor skills, sweating, hand-visual coordination, ocular vasodilation, conjunctival and / or scleral redness, intraocular pressure fluctuations, sinus tachycardia, cardiac arrhythmias, skin conductance / impedance levels, seizures, electromyography (EMG), electrocardiogram (ECG), photoplethysmography (PPG), galvanic skin response (GSR), blue-brown visual impairment, H-mask visual impairment, latent auditory impairment, and visual latency Presence obstruction, Stroop color word, simple response (conflict task), cognitive set switching, logical reasoning, decision time, rapid information processing, perceptual maze, simulated driving, visual search, time estimation, time perception, visual search, attentional search, symbol copying, letter cancellation, alphabet deletion, D2 cancellation, Brickenkamp D2, digit copying test (DDCT), symbol-digit substitution test (SDST), digit-symbol substitution test (DSST), digit vigilance, vigilance, auditory vigilance test, Wesness / Warburton vigilance task, rapid information processing, CRT + tracking split attention, selective attention, focused attention task, emotional attention task WAIS tests include: auditory flutter fusion, flash fusion, critical flicker fusion (CFF), attention continuity, paired associative learning, word list learning, 15-word test, introduction adjustment, delayed word recall, delayed word recognition, delayed picture recognition, word presentation, word recognition, numerical working memory, numerical memory, memory scanning, auditory Brown / Peterson test, visual Brown / Peterson test, visuospatial memory, fragment picture test, Pauli test, block span, number span, number span (forward), number span (backward), WAIS vocabulary, WAIS similarity, word fluency, verbal fluency, performance time (delayed word recognition), and more. Performance time (numerical working memory), performance time (digital awareness), performance time (rapid information processing), performance time (delayed image recognition), performance time (visual information processing), simple reaction time CRT, composite RT visual, visual selection RT, VRT, visual response speed, ART, auditory RT, wire maze tracing, Archimedes spiral, crisis tracking task, trajectory creation, tracking composite, tracking Wiener device, closure flexibility, WAIS block planning, WAIS image comparison, digit copying, manipulative motor skills, fine motor skills, handwriting analysis, tapping, hand-arm lateral reach alignment.This includes, but is not limited to, visual random reach of the arm, motor control and coordination, motor behavior, and EEG.

[0266] In the context of cannabis-derived pharmaceutical agents, a comprehensive description of non-invasively detectable biomarkers is, but is not limited to, Non-Patent Document 4, which is incorporated herein by reference to the extent that its entirety is fully presented herein.

[0267] In the context of some embodiments of this disclosure, evaluation, observation, or recording of personally perceived desirable / therapeutic effects and / or personally perceived undesirable / adverse effects may be available at any time when non-invasive biomarkers are unavailable to the patient or physician, for the purpose of monitoring PD effects to define a predetermined vaporization rate during initial calibration and / or to adjust that rate during self-titration or personalization of the device used for therapeutic purposes. Alternatively, the user or physician may choose not to use non-invasive biomarkers for any reason. Where necessary, an invasive biomarker measuring device may be used to monitor the amount of at least one pharmacokinetic effect and / or at least one pharmacodynamic effect induced by the drug in the patient, particularly if it is already implanted in or on the patient's body surface. In some embodiments, at least two of the perceived effects, non-invasive biomarkers, and invasive biomarkers are used to measure and / or estimate the same or different PD effects induced by one or more pharmaceutically active drugs in the user. It should be noted that sensors for monitoring PD effects may be used as part of a manual and / or automated feedback process to determine and / or adjust the predetermined vaporization rate of the drug offline or in real time.

[0268] As used herein, the term “real time” refers to a reference (recording, detection, measurement, reporting, depiction, response, etc.) to one or a series of events, where the reference is made essentially simultaneously and / or at the same rate as the event(s) in question. “Simply simultaneously and / or at the same rate” means that the time difference between a single event and its corresponding reference is in the range of response time: 0–30 minutes (0–30 min), 0–20 minutes, 0–10 minutes, 0–5 minutes, 0–1 minute, 0–45 seconds, 0–30 seconds, 0–20 seconds, 0–10 seconds, 0–5 seconds, 0–1 second, 0–750 milliseconds, 0–500 milliseconds, 0–250 milliseconds, 0–100 milliseconds, 0–50 milliseconds, 0–10 milliseconds, or 0–1 millisecond.

[0269] Where necessary, “real time” refers to a reference (recording, detection, measurement, reporting, depiction, response, etc.) to one event or a series of events, the reference basically occurring between the administration of the active agent and the disappearance of at least one pharmacodynamic effect induced by the administered agent in the subject. In some embodiments, “real time” refers to a reference to one event or a series of events, the reference occurring between two drug delivery inhalation events planned to occur between the administration of the active agent and the disappearance of at least one pharmacodynamic effect induced by the administered agent in the subject. Where necessary, the “real time” event or series of events includes a step of adjusting the timing and / or amount of the later drug delivery inhalation event according to data showing one or more effects of the earlier drug delivery inhalation event. In some embodiments, such disappearance means that the effect has reached a point where it is not detectable by a given sensor and / or user perception, in some cases.

[0270] In the context of embodiments of the present invention, the term “real-time measurement” refers to a reference made by a sensor in response to an event occurring in a subject communicating with the sensor. In some embodiments, real-time measurement is continuous, sporadic, regular, or systematic monitoring, reporting, recording, analysis, processing, presentation, display, and transmission of pharmacodynamic effects by a designated sensor communicating with a subject.

[0271] While some PD effects, such as the self-reported level of symptoms, are fundamentally subjective, the assessment of some PD effects has been standardized to provide objectivity, or at least to provide a comparative scale that can be generalized across the entire subject population, as is the case with pain scales where changes in pain level are considered to be the PD effect.

[0272] Pain scale protocols are available in various forms and can be used for newborns, infants, children, adolescents, adults, the elderly, and individuals with communication difficulties.Examples of pain scale protocols include the Alder-Hey Triage Pain Score, Behavioral Pain Scale (BPS), Brief Pain Indicator (BPI), Nonverbal Pain Indicator Checklist (CNPI), Critical Care Pain Observation Tool (CPOT), Comfort Scale, Dallas Pain Questionnaire, Descriptive Discrimination Scale (DDS), Dental Pain Indicator (DPI), Edmonton Symptom Assessment System, Faith Pain Scale-R (FPS-R), Face-Leg-Activity-Crying-Mood Scale, Lequesne Algofunctional Index, McGill Pain Questionnaire (MPQ), Neck Pain and Disability Scale (NPAD), and Numerical 11-point Box (B) (BS-11), Numerical Rating Scale (NRS-11), Oswestry Disability Index (ODI), Palliative Care Outcomes Scale (PCOS), Roland-Morris Back Pain Disorder Questionnaire (RMDQ), Support Team Assessment Schedule (STAS), Wong-Baker Faith Pain Rating Scale, Visual Analog Scale (VAS), Disease Specific Pain Scale (DSPI), Pediatric Pain Questionnaire (PPQ), Premature Infant Pain Profile (PIPP), Schmidt Sting Pain Index, Starr Sting Examples of such measures include, but are not limited to, the Sting Pain Scale, the Pain Self-Efficacy Questionnaire (PSEQ), the Patient-Specific Functional Scale (PSFS), the Colorado Behavioral Numerical Pain Scale (for sedated patients), AUSCAN: disease-specific and assessment of outcomes for osteoarthritis of the wrist, WOMAC: disease-specific and assessment of outcomes for osteoarthritis of the knee, and the Osteoarthritis Research Society International - Outcome Measures in Rheumatoid Arthritis Clinical Trials (OARSI-OMERACT) initiative.

[0273] As a non-limiting example, the Numerical Rating Scale (NRS-11) is an 11-point scale for patients to self-report pain in adults and children aged 10 and older, providing a numerical pain level: 0 for no pain; 1-3 for mild pain (anxiety, irritability, some impairment of ADL); 4-6 for moderate pain (significant impairment of activities of daily living or ADL); and 7-10 for severe pain (physical disability; inability to perform ADL).

[0274] In another non-limiting example, a visual analogue scale or visual analogue scale (VAS) is a psychometric response scale that can be used in questionnaires or interactive patient interfaces; the scale is a measure of subjective characteristics or attitudes that cannot be measured mechanically, chemically, or physically. When answering questions on a VAS, respondents specify their level of agreement to a description by indicating a position along a continuous line between two endpoints. This continuous (or "analog") aspect of the scale is what distinguishes it from discontinuous scales such as the Likert scale. There is evidence that visual analogue scales have superior measurement characteristics than discontinuous scales, making it possible to apply a wider range of statistical methods to the measurement. VAS can be compared to other linear scales such as the Likert scale or the Borg scale, but the sensitivity and reproducibility of the results are very similar. However, VAS can sometimes be more practical and useful than other scales.

[0275] Techniques that enable the objective measurement of pain and combine some of the aforementioned biomarkers are provided, for example, in Patent Documents 12 and 13, which are incorporated herein by reference to the extent fully presented herein. These techniques are designed for pain classification and monitoring in responsive subjects who are awake, semi-awake, or sedated.

[0276] Other non-invasive biomarker level determination techniques, such as an automated facial recognition system for pain level assessment [Non-Patent Literature 5; Non-Patent Literature 6] and a miniature cordless EMG measurement system for pain and other biomarker assessment [Non-Patent Literature 7], can be integrated into the methods presented herein via interfaces and systems, as shown below.

[0277] Invasively detected biomarkers include indicators that require sensors to be placed inside the patient's body, such as through skin penetration, or indicators that require samples to be taken from inside the patient's body to quantify them. For example, the use of a needle or blood extraction from a patient's vein via skin puncture to measure the concentration of any indicator or factor (biomarker) is considered an invasive measurement, and therefore these biomarkers are considered invasively detected biomarkers.

[0278] Self-titration: If a patient feels for any reason that the pre-set dose and / or regimen is insufficient, they may wish to readjust the prescribed vaporization rate (dose and / or regimen) of the drug, regardless of whether the prescribed vaporization rate (pre-set dose and / or regimen) has been individually induced for that patient, in accordance with their current physiological and mental state, or for any other reason. This option is considered drug self-titration and is part of the manual feedback process for determining the prescribed vaporization rate of the drug.

[0279] Therefore, if the PD profile requires re-selection, the lung delivery of the active drug from the MDI device further includes a step that allows the patient to self-titrate a predetermined vaporization volume, or a step that allows the physician to change and readjust the predetermined vaporization volume of the drug as needed.

[0280] According to some embodiments of any of the embodiments of the present disclosure, lung delivery of a pharmaceutically active drug further includes the step of configuring the device to deliver a controlled vaporization volume of the drug, the controlled vaporization volume being selected such that a re-selected pharmacodynamic profile of the drug is shown in the patient, thereby, at configuration, the controlled vaporization volume becomes a predetermined vaporization volume, and the re-selected pharmacodynamic profile is considered to be a pre-selected pharmacodynamic profile.

[0281] In some embodiments, the readjustment is performed without redetermining the PK and / or PD effects in the patient.

[0282] Automatic feedback: According to some embodiments, the adjustment or readjustment of a predetermined vaporization rate of a drug (drug dosage and regimen) includes an automated feedback process based on individual pharmacodynamic parameter data.

[0283] Individual pharmacodynamic parameter data may include therapeutic effects perceived by at least one individual and adverse effects perceived by at least one individual; and may also include at least one biomarker level data.

[0284] As previously stated, the automatically obtained biomarker level may be either an invasive or non-invasive biomarker. According to embodiments of this disclosure, the automatically obtained biomarker level is that of a non-invasive biomarker.

[0285] Therefore, in some embodiments of the embodiments of this disclosure, the method further includes: A process of automatically measuring, acquiring, or determining at least one personal pharmacodynamic parameter in a patient in the form of perceived therapeutic effects and / or perceived adverse effects and / or levels of at least one biomarker, which are collectively referred to herein as personal pharmacodynamic feedback data or information; A process of automatically redetermining the adjusted vaporization amount of a drug based on automatically acquired individual pharmacodynamic feedback data, or generally adjusting the dosage and regimen according to the acquired individual pharmacodynamic feedback data; The process includes delivering a controlled vaporization volume and automatically configuring the device so that a pre-selected or re-selected PK and / or PD profile is shown in the patient; As a result, for that particular individual, the adjusted vaporization amount becomes the predetermined vaporization amount of the pharmaceutical active agent, and the re-selected PK and / or PD profile becomes the pre-selected PK and / or PD profile.

[0286] In this specification, automatic determination of any PD effect, or automatic determination of the vaporization amount of a pharmaceutically active agent, is fully or partially applicable to any embodiment of this disclosure, and these include initial calibration of the MDI device, reconfiguration of the device during the personalization process, and / or a self-titration process.

[0287] Co-administration (simultaneous administration): In this specification, according to some embodiments of any of the embodiments of the present disclosure, the method and / or apparatus is suitable for the pulmonary delivery of multiple pharmacologically active drugs to a patient, and the apparatus is configured to deliver a predetermined vaporization amount of each drug separately, controllably, accurately, and reproducibly.

[0288] In some embodiments, co-administration of multiple active agents is performed to achieve a desired balance between therapeutic (desirable; positive; necessary) effects and adverse (undesirable; negative; unnecessary) effects. Such a balance can be achieved, for example, when one active agent has the ability to reduce adverse effects caused by other co-administered active agents while exhibiting some or no direct therapeutic effect. In another example, different active agents induce similar and cumulative desirable effects and different and non-cumulative undesirable effects; in this case, co-administration of such two agents makes it possible for the desired effects to be induced cumulatively (e.g., twice) and the undesirable effects to be induced substantially less (e.g., individually) compared to twice the dose of each administered individually. If necessary, the second agent has the effect of reducing and / or altering the nature of the adverse effects of the first agent. In such cases, it is also possible to increase the amount of the first agent (and the desired effect itself) to reduce, and possibly decrease, its undesirable effects without increasing them. This approach allows for higher doses to achieve the desired therapeutic effect while maintaining a low level of adverse effects.

[0289] According to some embodiments, these two or more agents can be contained in the same substance or in multiple substances. In some embodiments, at least one of the agents is present in at least one plant material. Accordingly, according to some embodiments, the apparatus and methods presented herein are configured to deliver each of at least two pharmacologically active agents separately in a predetermined vaporization amount, and the substance heated in the apparatus contains two or all of these pharmacologically active agents. Alternatively, the apparatus contains multiple substances containing pharmacologically active agents.

[0290] In some embodiments, a method is provided for delivering at least a first pharmacologically active agent and a second pharmacologically active agent to a subject through the lungs, wherein at least one of the agents is present in at least one plant material; the method is carried out by delivering the agents separately to the subject using a metered-dose inhalation device configured to vaporize at least a first predetermined vaporization amount of the first agent and at least a second predetermined vaporization amount of the second agent when the plant material is controlledly heated, the heating is performed so that the first predetermined vaporization amount is delivered continuously, simultaneously, and / or at least partially overlapping with the second predetermined vaporization amount, and each predetermined vaporization amount of the agent separately induces at least one pharmacokinetic effect and / or at least one pharmacodynamic effect in the subject.

[0291] According to one aspect of several embodiments of the present disclosure, a method is provided for delivering at least a first pharmacologically active agent and a second pharmacologically active agent to a subject via the lungs, wherein at least one of these active agents is present in at least one plant material; the method is: This is carried out by separately delivering drugs to a subject using a metered-dose inhalation device configured to vaporize at least a first predetermined vaporization amount of a first drug and at least a second predetermined vaporization amount of a second drug when at least one type of plant material is controlledly heated. In this method, heating is performed so that a first predetermined vaporization amount is delivered to the subject in a continuous, simultaneous, and / or at least partially overlapping manner with a second predetermined vaporization amount, and each predetermined vaporization amount of the drug separately induces at least one pharmacokinetic effect and / or at least one pharmacodynamic effect in the subject.

[0292] The pulmonary delivery of multiple active agents to a subject (patient) is generally known in the art as co-administration. As used herein, the term "co-administration" refers to the simultaneous administration of multiple active agents to a subject, but in the context of the embodiments presented herein, the term "simultaneous" means that the co-administered active agents are present in the subject (PK) or induce an effect (PD) at similar, identical, or partially overlapping times. In some embodiments, the time interval between the delivery of at least one agent (first) and the delivery of at least one other agent (second) is in the range of 0 to 30 minutes.

[0293] In the context of simultaneous administration of multiple active agents, the terms “substantially simultaneous” and “continuously” correspond to the terms “simultaneous” and “partially overlapping” as used herein, meaning that the time between the inhalation of the first agent and the inhalation of the second agent is short enough to be considered a single inhalation. If necessary, multiple inhalations are performed within 5 to 30 minutes. If necessary, each such “continuous” inhalation delivers one or more pharmaceutically active agents of different amounts or compositions to the user. If necessary, two or more inhalations provide one or more pharmaceutically active agents of the same composition and amount. In some embodiments, the inhalation of the second agent is performed at a time such that the previously inhaled first active agent still induces at least one PD effect in the subject. In some embodiments, simultaneous administration by continuous delivery of multiple active agents means that the inhaled agents produce essentially the same effect as if they were inhaled as a single inhalation.

[0294] According to some embodiments, the time interval between the delivery of the first drug and the delivery of the second drug is in the range of 0 to 30 minutes.

[0295] According to some embodiments, each of these agents can be delivered in a predetermined vaporization amount. Accordingly, the apparatus and methods presented herein are capable of delivering multiple predetermined vaporization amounts, which may be the same or different.

[0296] According to some embodiments, each of these agents can be delivered at predetermined time intervals. Thus, the apparatus and methods presented herein are capable of delivering multiple predetermined vaporization amounts at predetermined time intervals, and these time intervals may be the same or different.

[0297] According to some embodiments, the apparatus and methods presented herein are capable of delivering each of a plurality of predetermined vaporization amounts of pharmacologically active agents, and are designed to do so, where the predetermined vaporization amounts and predetermined time intervals may be the same or different from each other.

[0298] In some embodiments, co-administration is based on the interdependence of one or more PD effects induced by individual drugs, i.e., the PD effect of one drug influences the level of PD effects induced by other drugs. For example, in some embodiments, a predetermined vaporization amount of the first drug influences the level of the pharmacodynamic effect induced by the second drug. If necessary, a predetermined vaporization amount of the first drug enhances the level of the desired effect induced by the second drug. If necessary, a predetermined vaporization amount of the first drug reduces the level of the undesirable effect induced by the second drug. In some cases, the first and second drugs synergistically induce a desired effect.

[0299] In some embodiments, the method of delivering the multiple active agents presented above to the lungs may further include: The process includes adjusting at least one of a first predetermined vaporization volume and a second predetermined vaporization volume to achieve a predetermined pharmacokinetic effect and / or predetermined pharmacodynamic effect based on data showing that the drug induces at least one pharmacokinetic effect and / or at least one pharmacodynamic effect in a subject.

[0300] In some embodiments, the method further includes the step of generating index data by monitoring at least one pharmacokinetic effect and / or at least one pharmacodynamic effect induced in a subject by at least one of the first and second drugs.

[0301] As a non-limiting example, the co-administration of THC and CBD can be carried out using the apparatus and methods provided herein. In this example, the pain management regimen is performed by inhaling THC six times daily at a predetermined vaporization dose of 5 mg. This is combined with the inhalation of 300 mg of CBD three times daily to treat inflammation. The two pharmacologically active agents may be administered simultaneously or sequentially, i.e., in 6 to 9 inhalation sessions.

[0302] According to one aspect of several embodiments of the present disclosure, a method is provided for vaporizing at least a first pharmacologically active agent and a second pharmacologically active agent, at least one of these agents present in at least one plant material, suitable for pulmonary delivery to a patient, the method being carried out using a metered-dose inhalation device configured to vaporize at least a first predetermined vaporization amount of the first agent and at least a second predetermined vaporization amount of the second agent, the first predetermined vaporization amount being delivered to the subject in a continuous, simultaneous, and / or at least partially overlapping manner with the second predetermined vaporization amount, and the second predetermined vaporization amount being delivered to the subject in a separate manner.

[0303] According to one aspect of several embodiments of the present disclosure, the use of a metered-dose inhalation device is provided for vaporizing at least a first pharmacologically active agent and a second pharmacologically active agent, at least one of these agents present in at least one plant material suitable for pulmonary delivery to a patient, the device being configured to vaporize at least a first predetermined vaporization amount of the first agent and at least a second predetermined vaporization amount of the second agent when the plant material is controlledly heated, the heating being performed such that the first predetermined vaporization amount is delivered to the subject in a continuous, simultaneous, and / or at least partially overlapping manner with the second predetermined vaporization amount, and the pulmonary delivery of the agents to the subject, each of the predetermined vaporization amounts of the agent separately induces at least one pharmacokinetic effect and / or at least one pharmacodynamic effect in the subject.

[0304] Treatment method According to one aspect of several embodiments of the present disclosure, a method is provided for treating a patient suffering from a medical condition treatable by pulmonary delivery of a volatile pharmaceutically active agent. A method according to some embodiments of any of the embodiments of the present disclosure is carried out by pulmonary delivery of the agent to a patient from a metered-dose inhalation device configured to release at least one predetermined vaporized amount of the agent when a solid substance containing the agent is controlledly heated. According to some embodiments, the predetermined vaporized amount of the agent is selected to exhibit at least one pre-selected pharmacokinetic profile and / or at least one pre-selected pharmacodynamic profile of the agent in the patient.

[0305] Non-limited, representative medical conditions treatable by pulmonary delivery of volatile pharmaceutically active agents include neuropathic pain, phantom limb pain, nociceptive pain, cardiac pain (psychopathic pain or somatoform pain), asthma, chronic obstructive pulmonary disease (COPD), Crohn's disease, multiple sclerosis (MS), febrile seizures plus generalized epilepsy (GEFS+), spasticity, Dravet syndrome, seizures, epilepsy, psychiatric disorders, anxiety disorders, post-traumatic stress disorder (PTSD), insomnia, delirium, elevated intraocular pressure, bladder dysfunction, tics, Tourette's syndrome, eccentric needs, sexual dysfunction, inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), hypertension, sepsis and cardiogenic shock, drug dependence and cravings, tremors, and other movement disorders.

[0306] According to some embodiments of the embodiments of the present disclosure, the method is carried out using an MDI device configured to release a predetermined vaporization amount such that the deviation of the actual vaporization amount of the agent from a predetermined vaporization amount of the agent is 20% or less, 15% or less, 10% or less, or 5% or less of the predetermined vaporization amount.

[0307] According to some embodiments of the embodiments of this disclosure, the method is carried out such that the deviation of the actual pharmacokinetic profile from a pre-selected pharmacokinetic profile is 40% or less of the pre-selected pharmacokinetic profile. Alternatively, the deviation may be 35% or less, 30% or less, 25% or less, or 20% or less. The deviation is the pharmacokinetic profile, or, for example, C t Or C max It should be noted that such deviations may be included in one or more pharmacodynamic parameters, including profiles such as those mentioned above. Such deviations are expected to be low due to the low intervariability of PK effects obtained when using accurate, consistent, and precise MDI devices.

[0308] According to some embodiments of the embodiments of this disclosure, the method is carried out such that the deviation between the perceived PD profile and a pre-selected PD profile at a given time is 25% or less, 20% or less, 15% or less, 10% or less, or 5% or less. The deviation between the perceived PD profile and the pre-selected PD profile at a given time can be evaluated by determining the PD effect as described above. The deviation is expected to be low due to the low mutual variation of the PK effects as described above.

[0309] Since the device can be configured to consistently deliver any precise amount to produce a pre-selected PD effect or a predetermined PD effect in the patient, the device and method presented herein can implement a pre-selected PD profile or a predetermined PD profile, and this profile can be finely controlled as follows: Within a range lower than the minimum level of the desired effect (e.g., below the treatment window; see Figure 8, the area below the lower horizontal dashed line); Within the range from the minimum level of the desired effect to the maximum level of the desired effect, and within the range where undesirable effects are tolerable and / or acceptable, i.e., substantially low, absent, or not perceived (e.g., within the treatment window; see Figure 8, the area between the upper and lower horizontal dashed lines); and Within a range higher than the minimum level of undesirable effect (e.g., above the treatment window; see Figure 8, the area above the lower horizontal dashed line).

[0310] In some embodiments, the minimum level of adverse effect corresponds to the maximum level of therapeutic effect at which no adverse effect is detected or perceived.

[0311] In some embodiments, a pharmacodynamic profile level higher than the minimum level of adverse effect is a level where a higher level of adverse effect is an acceptable level. One of an individual's therapeutic and legal factors may determine the acceptable level of adverse effect, such as personal preferences, habits and endurance, pharmaceutical and professional safety considerations, and legal and social considerations.

[0312] In some embodiments, “minimum therapeutic effect” means the minimum detectable therapeutic effect. In some cases, such a minimum level is sufficient to justify treating an individual with a given dose and / or regimen of at least one substance. Such justification may be based, for example, on the type and severity of adverse effects, and the minimum level of effect the treatment may have on the patient's health. In some cases, minimum therapeutic effect means the minimum effect perceived by the treated individual. In some cases, justification for administering doses and / or regimens aimed at PK / PD effects below the therapeutic window may be considered to be achieving prophylactic treatment, or mitigating the outcome of acute pain (breakthrough pain), and / or preventing the development of tolerance to the treatment.

[0313] As described above, according to some embodiments of any of the embodiments of this disclosure, the pre-selected PD profile corresponds to the therapeutic window of the drug in the patient, that is, it is within a range from the minimum level of therapeutic effect to the maximum level of therapeutic effect in which adverse effects are acceptable.

[0314] In any pre-selected PD profile, the method and apparatus provide high accuracy and reproducibility; therefore, according to some embodiments of the embodiments of the present disclosure, the deviation of the perceived pharmacodynamic profile from the pre-selected pharmacodynamic profile at a given time point is 25% or less, 20% or less, 10% or less, or 5% or less below the pre-selected PD profile, and / or 25% or less, 20% or less, 10% or less, or 5% or less above the above pre-selected PD profile.

[0315] A non-limiting example of a medical condition that can be made tolerable by pulmonary delivery of volatile pharmacologically active drugs is pain that can be treated with THC vaporized from cannabis.

[0316] Metered dose inhalation (MDI) device: According to another aspect of some embodiments of the present disclosure, a metered-dose inhalation (MDI) device is provided configured to deliver a predetermined vaporized amount of at least one pharmacologically active agent to a patient's lungs, where: The apparatus is configured to deliver a predetermined vaporization amount of the above-mentioned agent when a solid substance containing the above-mentioned agent is controlledly heated; The predetermined vaporization volume is selected to provide a pre-selected pharmacokinetic profile and / or pre-selected pharmacodynamic profile of the drug in the patient; and The predetermined vaporization volume is derived by measuring at least one pharmacokinetic parameter and / or at least one pharmacodynamic parameter induced by lung delivery of the drug from an MDI device in the patient (PK / PD test).

[0317] According to one aspect of some embodiments of the present disclosure, a method for controlling a metered-dose inhaler is provided, the method of which: Heating a plant material to vaporize at least one pharmacologically active agent present in the plant material in a predetermined vaporization amount; and This is performed by controlling a predetermined vaporization amount based on data showing at least one pharmacodynamic effect induced by the drug in the subject.

[0318] According to one aspect of several embodiments of the present disclosure, a method for delivering at least one pharmacologically active agent present in a plant material to a subject via the lungs is provided; the method is: Selecting at least one predetermined vaporization amount of a drug to achieve at least one predetermined pharmacokinetic effect and / or at least one predetermined pharmacodynamic effect induced by the drug in the subject; and This is carried out by using a quantitative inhalation device to vaporize a predetermined amount of at least one agent in order to control the heating of a plant material.

[0319] According to some embodiments of the present invention, the MDI device is further configured to communicate with a patient interface circuit and is integrated into a system designed to allow patient and / or physician to acquire and input PK / PD data, store patient records, perform automatic or manual calibration and adjustment, and reset and re-determine the initial presets of the device, as described in detail below.

[0320] As described above and demonstrated in the PK / PD trials presented in the Examples section below, the inter-cohort variability of PK / PD in the study was remarkably low, made possible by the use of accurate and consistent MDI devices according to the embodiments of this disclosure.

[0321] According to some embodiments of any of the embodiments of this disclosure, the methods and apparatus presented herein are also characterized by high accuracy, consistency, precision, and reproducibility, which are achieved by minimizing the deviation between the actual amount of drug inhaled by the patient and a predetermined amount of drug vaporized.

[0322] According to some embodiments of the embodiments of this disclosure, an MDI apparatus for controlling the vaporization of at least one active pharmaceutical agent from at least one substance by heating is: At least one cartridge (also referred to herein as a “dose unit”) containing a substance comprising at least one active pharmaceutical agent; A heating element adapted to heat the substance and vaporize the pharmaceutical active agent; and It features a mechanism adapted for moving the cartridge relative to the controller to supply power to the heating element.

[0323] In one embodiment of the present invention, the device further contains a substance configured as a plurality of cartridges arranged in a tape, DAISY, or magazine, the substance containing an active pharmaceutical agent. Optionally, the active pharmaceutical agent is a limited pharmaceutical agent. Optionally, or further, the active pharmaceutical agent is selected from the group consisting of: tetrahydrocannabinol (THC), salvinorin A, benzoylmethylecgonine, dimethyltryptamine, and psilocybin. Optionally, or further, the substance consists of a predetermined amount of the active pharmaceutical agent per unit area of ​​each cartridge in the tape, DAISY, or magazine. Optionally, or further, the thickness of the cartridges is in the range of approximately 0.2 mm to approximately 2.0 mm. Optionally, or further, the tape, DAISY, or magazine contains approximately 5 grams to approximately 100 grams of the substance. Optionally, or further, the tape, DAISY, or magazine contains an amount of the active pharmaceutical agent sufficient for at least two treatments. Optionally, or further, the cartridge comprises a first material layer in contact with the substance, the first layer having holes large enough to release gas and small enough to retain residue of the heated substance. Optionally, or further, the diameter of the holes is in the range of 25 μm to 500 μm. Optionally, or further, the cartridge comprises a second material layer connected to the substance, the second layer configured to conduct heat to the substance without transferring significant heat to the entire second layer. Optionally, or further, the heating element and substance are held between the first and second layers.

[0324] In one embodiment of the present invention, the apparatus further comprises an inhalation unit, the inhalation unit comprising a mouthpiece for inhaling a pharmaceutically active agent, the mouthpiece being in fluid communication with a vapor chamber of the apparatus, the vapor chamber containing a vaporized active pharmaceutically active agent.

[0325] If necessary, the mouthpiece is equipped with a one-way valve to control the flow rate of the fluid exiting the vapor chamber. If necessary, or in addition, the device further comprises a sensor in fluid communication with the mouthpiece, the sensor being adapted to estimate the airflow velocity and send a signal to a controller, the controller being adapted to vaporize the pharmaceutical active agent according to the airflow velocity.

[0326] In one embodiment of the present invention, the apparatus further comprises a controller configured to synchronize heating with the operation of the cartridge and / or the airflow velocity due to suction.

[0327] In one embodiment of the present invention, the apparatus further includes a circuit (controller) for controlling the activation of the heating element.

[0328] In one embodiment of the present invention, the device further comprises a communication interface for communicating with one or more external computers and / or systems and / or patient / physician interfaces.

[0329] In one embodiment of the present invention, the device further includes a dose display meter for visually outputting the vaporization of a pharmaceutical active agent.

[0330] In one embodiment of the present invention, the device is portable and weighs 300 grams or less.

[0331] In one embodiment of the present invention, the apparatus further comprises a memory configured to hold at least one of prescription data and usage data, the memory being connected to a controller, the controller being adapted to control at least one of heating elements and mechanisms according to dosage and / or regimen data.

[0332] In one embodiment of the present invention, the device further has a unique ID adapted to track device usage by the relevant patient.

[0333] In one embodiment of the present invention, the device further comprises sensors adapted to detect physical damage to the device.

[0334] A method for controlling the vaporization of an active pharmaceutical agent from a substance is provided according to one embodiment of the present invention, wherein the substance is configured as a cartridge, and the method includes; The process includes heating a region of the cartridge to vaporize a predetermined amount of active pharmaceutical agent, and moving the cartridge relative to a heat source.

[0335] Alternatively, the heating element is housed within a cartridge, and the cartridge moves relative to electrical contacts to supply power to the heating element.

[0336] In one embodiment of the present invention, the method further includes the step of adjusting at least one of the timing and rate of movement for vaporizing an active pharmaceutical agent according to a delivery profile. Optionally, the substance includes a macroscopic plant structure.

[0337] In one embodiment of the present invention, vaporization includes vaporization during lung delivery.

[0338] In one embodiment of the present invention, heating includes heating that reaches a target temperature in less than 500 milliseconds from the start signal.

[0339] A method for controlling the vaporization of at least one active pharmaceutical agent from at least one substance by heating is provided according to one embodiment of the present invention, the method comprising: The process includes heating multiple regions of a substance constructed as one or more cartridges with a single user trigger to release at least one active pharmaceutical agent.

[0340] If necessary, the above region may contain multiple different active pharmaceutical agents.

[0341] A method for manufacturing a cartridge containing an active pharmaceutical agent is provided according to one embodiment of the present invention, the cartridge being adapted for use with a device for automatically local heating to vaporize the pharmaceutical agent, the method comprising: A process for pulverizing a substance without significantly damaging the active pharmaceutical agent; A process of sieving the pulverized material to isolate small particles; A step of measuring the concentration of an active pharmaceutical agent in the form of small particles; and This process includes pushing small particles into the cartridge.

[0342] In one embodiment of the present invention, sieving is performed multiple times to isolate particles of different sizes.

[0343] In one embodiment of the present invention, the particle size is in the range of approximately 100 μm to approximately 700 μm.

[0344] In one embodiment of the present invention, pressing is performed on a material having holes smaller than the size of small particles.

[0345] In one embodiment of the present invention, the method further includes the step of writing the concentration of an active pharmaceutical agent onto a cartridge.

[0346] A cartridge for therapeutic drug delivery containing a substance comprising an active pharmaceutical agent is provided according to one embodiment of the present invention, wherein the substance is constructed together with a predetermined amount of the active pharmaceutical agent per unit area of ​​the tape (cartridge), and a heating element is provided within the cartridge.

[0347] In one embodiment of the present invention, multiple cartridges are constructed as tape rolls, DAISY tapes, or magazines.

[0348] Illustrative use: According to some embodiments and aspects of this disclosure, each of the methods, apparatus, interfaces, systems, or subsystems presented herein can be used to treat medical conditions treatable by a pharmacologically active agent that can be vaporized from a solid material. In some embodiments of this disclosure, the material is a plant-based material.

[0349] Several plant species available in the context of this disclosure include Cannabis sativa, Cannabis indica, Cannabis ruderalis, Acacia, Amanita muscaria, Yahe, Belladonna, Betel nut, Brugmansia, Brunfelsia japonica, Aesculus sibirica, Banisteriopsis carpi, Trichocereus, Cacao, Capsicum, Cestrum, Cocaine, Coleus, Aruncus dioicus, Coffee plant, Datura, and Desfontainea. Genus, Dipropterus cabrerana, Chinese laurel, Baccaratus, Guarana, Morning glory, Hemerocallis, Ipomoea, Lagochilus inebrians, Justicia pectralili, Selenium tortosum, Kawakawa, Arabian tea, Opium tree, Flame lily, Nymphaea, Nelumbo, Texas mountain laurel, Lime bean, Mandragora, Mimosa tenuiflora, Yellow beach morning glory, Psilocybe, Laughing mushroom, Nutmeg Turvina colibosa, Passiflora japonica, Phragmites australis, Phragmites australis, Picchuli, Poppy, Psychotria viridis, Salvia divinorum, Sakena, Trichocereus pachanoi, Sinikui, Sleepygrass, Solandra, St. John's wort, Harmala, Triennale, Tea plant, Nicotiana tabacum, Rusticum, Virola seidra, Boacantha africana, Wild lettuce, Wormwood This includes, but is not limited to, mate, Ana denanthera species, yohimbe, Kalea, coffee plants (Rubiaceae), Sapindaceae, Camellia, Malvaceae, Aquifoliaceae, Hoodia, German chamomile, Passiflora incarnate, tea plant, peppermint, spearmint, European raspberry, eucalyptus, lavender, thyme, lemon balm, and any part or combination of these.

[0350] In the context of embodiments of this disclosure, other plants and botanical materials that can be usefully used to vaporize at least one pharmaceutically active agent include: aloe vera, angelica, anise, ayahuasca (banisteriopsis carpi), barley, black mint, blue lotus, burdock, chamomile, caraway, cat's claw, clove, comfrey, corn silk, ryegrass, damiana, dandelion, ephedra, eucalyptus, evening primrose, fennel, feverfew, fringe tree, garlic, ginger, ginkgo, ginseng, goldenrod, hydrastis, turmeric, green tea, guarana, hawthorn, hops, horsetail, and hibiscus. Sop, cola nut, kraton, lavender, lemon balm, licorice, lion's tail (wild daga), maca bulb, hollyhock, meadowsweet, milk thistle, motherwort, passionflower, passionflower, peppermint, thistle poppy, purslane, raspberry leaf, poppy, sage, saw palmetto, dwarf yam, cineraria lobata (Maya sun opener), spearmint, sweet flag, Syrian rue (Peganum harmara), thyme, turmeric, valerian, wild yam, wormwood, yarrow, mate, yohimbe, and any part or combination thereof.

[0351] In some embodiments, the active agent is a terpenoid, alkaloid, or cannabinoid. For example, in some embodiments, the active agent is a diterpenoid such as salvinorin A derived from salvia. In other embodiments, the active agent is an alkaloid such as benzoylmethylecgonine derived from the coca plant, or the active agent is a tryptamine such as psilocybin derived from mushrooms. In alternative embodiments, the active substance is dimethyltryptamine (DMT) derived from various plants. In further embodiments, the active substance is nicotine derived from tobacco. In further embodiments, the active substance is a terpenoid present in various plant forms, such as limonene, α-pinene, β-myrcene, linalool, β-caryophyllene, caryophyllene, nerolidol, or phytol.

[0352] According to some embodiments, the plant material is selected from the group consisting of Cannabis sativa, Cannabis indica, and Cannabis ruderalis, and according to some embodiments, the plant is Cannabis sativa.

[0353] Cannabis is a natural source of volatile cannabinoids, which comprise a diverse class of compounds that act on cannabinoid receptors found in human and other animal cells. Cannabinoids, including endocannabinoids (produced in animals), phytocannabinoids (found in cannabis and several other plants), and synthetic cannabinoids (chemically produced), are known to bind to natural receptor proteins and inhibit the release of neurotransmitters in the brain. The main psychoactive compound in cannabis is phytocannabinoid Δ 9 - It is tetrahydrocannabinol (THC).

[0354] Cannabidiol (CBD) is another major component of the plant, making up up to 40% of plant resin extracts. There are at least 85 cannabinoids isolated from cannabis, exhibiting diverse effects, including cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), cannabinodiol (CBDL), cannabicyclol (CBL), cannabiersoin (CBE), cannabitriol (CBT), cannabidivarin (CBDV), tetrahydrocannabivarin (THCV), and many others.

[0355] Tetrahydrocannabinol (delta-9-tetrahydrocannabinol; Δ 9 - THC (THC) is the main psychoactive component of the cannabis plant. 9 - THC and Δ 8THC mimics the action of anandamide, a neurotransmitter naturally produced in mammals. These two types of THC produce the cannabis-related psychoactive effects by binding to CB1 and CB2 cannabinoid receptors in the brain; they have been reported to exhibit nearly equal affinity for CB1 and CB2 receptors. While THC is known to relieve moderate pain (analgesic) and is neuroprotective, studies have also shown that THC reduces neuroinflammation and stimulates neurogenesis.

[0356] Cannabidiol (CBD) was previously thought to be non-psychoactive and not affect the psychoactive effects of THC. However, recent reports have shown evidence that smokers of cannabis with a high CBD / THC ratio are less likely to experience schizophrenia-like symptoms. This is supported by psychological tests in which participants experienced less severe psychotic-like effects when intravenously administered THC together with CBD.

[0357] Cannabidiol (CBD) has different affinities to CB1 and CB2 receptors compared to THC (CBD's affinity for CB2 receptors is stronger than its affinity for CB1 receptors), but it acts as an indirect antagonist of cannabinoid agonists. Recently, cannabidiol has been found to antagonist GPR55, a novel putative cannabinoid receptor expressed in the caudate nucleus and fruit pit. Cannabidiol has also been shown to act as a 5-HT1A receptor agonist, and this action is involved in its antidepressant, anxiolytic, and neuroprotective effects. CBD has also been reported to alleviate convulsions, inflammation, anxiety, and nausea.

[0358] CBD is known to play a role in preventing THC-related short-term memory loss in mammals. CBD has also been suggested as a potential treatment for schizophrenia. Researchers have discovered CBD's ability to "deactivate" the activity of ID1, a gene responsible for metastasis in breast cancer, particularly aggressive triple-negative breast cancer, and other types of cancer.

[0359] Therefore, according to some embodiments of this disclosure, the pharmacologically active agent is Δ 9 - A cannabinoid selected from the group consisting of tetrahydrocannabinol (THC), cannabidiol (CBD), cannabigerol (CBG), cannabichromene (CBC), cannabinol (CBN), cannabinodiol (CBDL), cannabicyclol (CBL), cannabiersoin (CBE), cannabidivarin (CBDV), tetrahydrocannabivarin (THCV), and cannabitriol (CBT), and according to some embodiments, the pharmacologically active agent is Δ 9 - Selected from the group consisting of tetrahydrocannabinol (THC) and cannabidiol (CBD).

[0360] As mentioned above, pulmonary delivery of cannabis-derived cannabinoids by smoking is the most common route of administration used by the majority of patients prescribed cannabis. The substantially lower oral and / or lower oral mucosal route of delivery of cannabis or its extracts is partly due to the slow and irregular absorption of cannabinoids by oral administration, which delays the onset of analgesia and often results in insufficient pain relief. However, smoking is a rapid and efficient method of cannabinoid delivery, and it has been shown that the first effects begin to appear after about 7 minutes. However, the bioavailability of tetrahydrocannabinol (THC) is heterogeneous, ranging from 2 to 56%, which is mainly due to variations in the depth of inhalation, duration of smoking, breath-holding time, and the assumption that about 30% of the THC dose is destroyed by thermal decomposition during smoking.

[0361] As described above, in order to improve the efficiency, accuracy, and consistency of inhaled cannabinoid administration while avoiding the risk of smoking-related diseases caused by harmful pyrolysis byproducts, some embodiments of the present disclosure are based on the use of non-combustion and smokeless MDI devices, such as those taught in Patent Document 1, which have been shown to be best suited for intrapulmonary administration of cannabis-derived cannabinoids.

[0362] In some embodiments, the lung delivery method described herein involves THC, or more specifically, Δ as a pharmaceutically active agent. 9 - Utilizes THC. In some embodiments, the THC dose (predetermined vapor volume) is approximately 0.1 to 10 mg and has been found to be a beneficial analgesic for various neuropathic pain conditions. Such low THC doses are available in cannabis. 9 - Depending on the total amount of THC, it is possible to accurately and consistently vaporize natural cannabis in amounts ranging from 5 to 50 mg, 6 to 50 mg, 7 to 40 mg, 8 to 40 mg, 8 to 30 mg, 9 to 40 mg, 9 to 35 mg, 10 to 35 mg, 11 to 30 mg, 12 to 30 mg, 12 to 27 mg, or 12 to 25 mg. In some preferred embodiments, cannabis has approximately 20% Δ 9 -Contains THC, and the amount of cannabis used in the inhaler for each dose ranges from 15.0 to 25.0 mg.

[0363] In some embodiments, Δ 9 - In cannabis samples containing THC, Δ 9 -When a single dose of 3.08±0.02 mg of THC was delivered via single inhalation as the total available amount of THC, the patient's Δ 9 - C of THC max Plasma levels rose to 38±10 ng / ml, pain intensity decreased by 45%, and returned to normal within 90 minutes.

[0364] As demonstrated by the PK / PD tests presented in the Examples section below, loading approximately 15 mg of cannabis aliquots into an MDI and heating each at approximately 190°C for less than approximately 3 seconds results in approximately 52% of the total usable amount for inhalation of plant material being Δ 9 -THC was generated. Such Δ 9 - High THC yields were measured in different types of smoking procedures known in the art. 9 - This is significant compared to the THC yield. For example, the Δ produced by smoking. 9 - Plasma levels of THC vary significantly, and plant-based materials are suitable for inhalation. 9-Only about 20-37% of the total THC is estimated to be extracted, with the remainder lost through combustion (23-30%) and sidestream smoke (40-50%). Furthermore, even when commonly used vaporizers and vaporization techniques such as Volcano® were applied, heating a 200 mg dose of cannabis crude top containing 18% THC to 200°C resulted in only 22% THC delivery. This difference in extraction efficiency among the various vaporizers, MDI devices and the methods described herein known in the art is based particularly on the diverse and unique mechanical attributes of the MDI that enable the precision and consistency required for its PK / PD calibration.

[0365] Among other advantageous properties of the methods and apparatus presented herein, which, according to some embodiments, involve a step of vaporizing cannabinoids from cannabis at temperatures of 155–218°C, it has been found that polynuclear aromatic hydrocarbons, as well as carbon monoxide, benzene, toluene, and particulate tar levels, were dramatically reduced in the cannabis vapor phase. This finding stands in stark contrast to the products produced during cannabis smoking. Although combustion products were not monitored, harmful intake from MDI devices used in accordance with this disclosure is expected to be minimal, if any. This expectation is based on the following observations: (1) Each dose consisted of a small amount (approximately 15 mg) of cannabis with a high THC concentration (approximately 20%); (2) Unlike burning cannabis that turns to ash, the appearance of the residue after evaporation was a uniform amber color; (3) No burning sensation in the upper respiratory tract was reported by patients; (4) No increase in cannabinol (a product of THC oxidation) was measured in the residue; (5) In the residue, Δ 9 - from Δ 8 - No conversion to THC was detected.

[0366] The inventors purified and quantified Δ 9 - Using THC, similar to those previously reported in the art, Δ 9- Demonstrated the PK / PD profile of THC. As demonstrated in the Examples section below, the inhalation method employed by the inventors successfully enables the pulmonary delivery of THC, which is characterized by rapid absorption, followed by a two-stage decrease in plasma concentration over time: a rapid decrease stage corresponding to the distribution and large-scale storage of THC in tissues, followed by a stage of sustained release and elimination from adipose tissue into the blood.

[0367] The inventors have found that for various delivery routes of cannabis, Δ obtained by smokeless inhalation according to the method described herein 9 - Peak plasma concentration of THC (C max ) is publicly known in the art C max The levels were compared. As discussed in the Examples section below, the inhalation method described herein involves the amount of C per 1 mg of THC available in the cannabinoid material used. max This resulted in the largest increase – the average was 12.3 ng / ml / mg THC, compared to 6.1–9.0 for the Volcano vaporizer and 0.6–4.6 for regular cigarettes. Furthermore, the inter-individual variability of peak THC concentration obtained by the method described herein was considerably lower than the inter-individual variability obtained in the art: 25.3%, compared to 47–85% for vaporizers, 32–115% for cigarettes, 42–115% for oral administration, and 59–67% for the oral mucosal delivery route.

[0368] Accordingly, in some embodiments, the pulmonary delivery method described herein provides enhanced analytical capability in determining and controlling the amount of pharmaceutically active agent. In some embodiments, for example, individual pre-selected vaporization amounts (dose) of THC are released electronically (by heating pre-weighed cannabis) in increments of 0.1 mg, within the ranges of 0.1-6.0 mg, 0.3-1.7 mg, 0.1-2.0 mg, 0.2-1.9 mg, 0.2-1.8 mg, 0.3-1.8 mg, 0.3-1.6 mg, 0.4-1.6 mg, 0.5-2.0 mg, 0.6-2.0 mg, or 0.3-0.9 mg, as well as any sub-range and any intermediate values ​​between these ranges.

[0369] According to embodiments of the methods provided herein, predictive PK / PD protocols are developed for vaporized cannabinoids based on clinical data accumulated individually for each patient in a patient cohort, and these protocols describe the doses and regimens administered based on the individual and population parameters described above. These protocols accurately mimic the patient's PK profile after delivery of a given dose or regimen, and in parallel predict the PD profile, which consists of symptom relief (therapeutic effect) and psychoactivity levels (adverse effect). Once the levels and adverse psychoactivity levels correlate with PK and patient parameters, a relatively narrow therapeutic window that the MDI device can accurately maintain in the patient is derived by automating a pre-selected specific vaporization amount (dose and / or regimen).

[0370] By inputting patient data, the protocol calculates the recommended dose and regimen for that particular patient to stay within a specific treatment window for a given period.

[0371] In one embodiment, the calculated doses and regimens for a 35-year-old male patient with a BMI of 22 to remain within a 3-hour treatment window were 1.2 mg at t=0; 1.0 mg at t=10 min; and 0.5 mg at t=60 min (see Figure 8).

[0372] According to these embodiments, the device selectively administers different doses at different time intervals in order to alleviate symptoms while preventing adverse effects.

[0373] Systems for lung delivery: As described above, the methods and apparatus presented herein are well suited to the personalization, self-titration, mechanization, and automation of other complex and challenging modes of administration and treatment for a variety of medical conditions; however, there are challenges to any personalized treatment protocol, and therapies based on the pulmonary delivery of active drugs vaporized by heat from natural substances remain an unmet challenge.

[0374] Once the accuracy, consistency, and reproducibility issues have been resolved using the MDI apparatus disclosed herein; and once the need arises to calibrate and pre-configure the apparatus to remain within a desired treatment window based on widely accepted PK / PD experimental parameters, the inventors have conceived of an integrated system capable of controlling the apparatus using input information collected from diverse sources in order to provide highly personalized and effective treatment for a given patient in real time.

[0375] According to one aspect of several embodiments of this disclosure, a system is provided, and the system is: A quantitative inhalation device for delivering at least one pharmacologically active drug present in a plant material to a subject in a predetermined vaporized amount by controllingly heating the plant material to vaporize a predetermined vaporized amount of the drug from the plant; and It includes a controller that is associated with the inhaler device and configured to control a predetermined vaporization rate.

[0376] According to one aspect of several embodiments of the present disclosure, a system is provided for delivering at least one pharmacologically active agent present in a plant material to a subject via the lungs, the system being: A quantitative inhalation device configured to vaporize at least one predetermined vaporization amount of a drug when a plant material is heated in a controllable manner; and The system includes a controller configured to select at least one predetermined vaporization amount of the drug in order to achieve at least one predetermined pharmacokinetic effect and / or at least one predetermined pharmacodynamic effect induced by the drug in a subject.

[0377] According to one aspect of several embodiments of the present disclosure, a system is provided for delivering at least a first pharmacologically active agent and a second pharmacologically active agent to a subject in the lungs, wherein at least one of the agents is present in at least one plant material; the system is; A metered-dose inhalation device configured to deliver drugs separately to a subject by heating at least one plant material to vaporize at least a first predetermined vaporization amount of a first drug and at least a second predetermined vaporization amount of a second drug; and A controller configured to perform heating of a first predetermined vaporization amount continuously, simultaneously, and / or at least partially overlapping with a second predetermined vaporization amount; Each of the predetermined vaporization amounts of the drug is selected to separately induce at least one pharmacokinetic effect and / or at least one pharmacodynamic effect in the subject.

[0378] According to one aspect of several embodiments of this disclosure, a system is provided, and the system is: A quantitative inhalation device for delivering at least one pharmacologically active drug in a predetermined vaporized amount to a subject's lungs by controllingly heating a plant material to vaporize a predetermined amount of drug from the plant; and It comprises a controller associated with an inhalation device configured to control a predetermined vaporization amount, The controller is configured to receive operation setting data regarding a predetermined vaporization amount from a remote control device. In some embodiments, the remote control device is configured to receive data indicating at least one pharmacodynamic effect induced by the drug in the subject, and to determine and transmit operation setting data regarding a predetermined vaporization amount.

[0379] According to one aspect of several embodiments of this disclosure, a system is provided, and the system is: A quantitative inhalation device for delivering at least one pharmacologically active drug in a predetermined vaporized amount to a subject's lungs by controllingly heating a plant material to vaporize a predetermined amount of drug from the plant; and It includes a controller associated with an inhalation device and configured to control a predetermined vaporization amount based on data showing at least one pharmacodynamic effect induced by the drug in a subject.

[0380] According to one aspect of several embodiments of the present invention, a system is provided comprising a quantitative inhalation device for delivering at least one predetermined amount of at least one pharmacologically active agent to a subject's lungs. The system further comprises at least one sensor for monitoring at least one pharmacodynamic effect, such as a psychoactive effect, induced by the agent in the subject; and a processing unit associated with the inhalation device and the at least one sensor. In some embodiments, the processing unit is configured to determine a predetermined amount based on data received from the sensor. The amount determined and controlled may be a single dose or a regimen.

[0381] Indicator data can be obtained from a variety of sources, including statistical data such as drug-induced pharmacodynamic effects within a population, user history, preferences and habits, and physician prescriptions. In some embodiments, indicator data can be obtained via at least one sensor configured to monitor the pharmacodynamic effects on a subject, and / or a user interface device configured to input data obtained from the sensor and / or other devices. In some embodiments, a controller is configured to receive indicator data regarding pharmacodynamic effects from the sensor and / or the user interface device.

[0382] According to some embodiments, the controller communicates directly and / or indirectly with sensors and / or interface devices. That is, the controller can associate indicator data (sensors and / or interface devices) with a source of information via direct communication, or it can associate it with a remote control device.

[0383] According to some embodiments, the system comprises the inhalation device described above, the controller described above, and at least one sensor and / or user interface described above, each independently configured to provide the controller with data indicating at least one type of PD effect induced by the active drug in a subject.

[0384] According to one aspect of several embodiments of this disclosure, a system is provided, and the system is: A quantitative inhalation device for delivering at least one pharmacologically active drug present in a plant material to a subject's lungs by controllingly heating the plant material to vaporize a predetermined amount of the drug from the plant; A sensor for monitoring at least one pharmacodynamic effect induced by a drug in a subject, and / or a user interface device for inputting data obtained from at least one sensor for monitoring at least one pharmacodynamic effect induced by a drug in a subject; The device comprises, but is not limited to, an inhalation device and a controller associated with at least one sensor.

[0385] In some embodiments, the controller used in the systems described herein is configured to control a predetermined vaporization rate by controlling the heating of a substance (e.g., a plant material). Controllable heating of a plant material is achieved, for example, by controlling at least one of the heating temperature, heating pattern (the portion of the plant material to be heated), heating rate (the number of times the plant material is heated), heating duration (the length of time the plant material is heated in any given heating event), and any combination thereof.

[0386] In some embodiments, the controller is configured to control a predetermined vaporization amount by controlling the airflow of the intake device, for example, by controlling the duct opening, valves, and shutters of the intake device.

[0387] In some embodiments, the controller is configured to control a predetermined vaporization volume by controlling the timing of one or more inhalation events. For example, the predetermined vaporization volume is delivered in multiple inhalation events, and the controller is configured to issue at least one alert signal to prompt the subject to use the inhalation device at a specified time, a specified time interval, and any other schedule, in order to complete the lung delivery of the predetermined vaporization volume to the subject.

[0388] In some embodiments, a controller is used to adjust a predetermined vaporization rate by controlling the heating and airflow parameters within the inhalation device, thereby achieving a predetermined pharmacokinetic and / or pharmacodynamic effect based on pharmacodynamic effects. In some embodiments, the controller is configured to perform the adjustment of the predetermined vaporization rate in real time.

[0389] Generally, controllers are used to implement more complex treatment plans, such as regimens and deliveries of multiple active agents, each with different dose and / or timing adjustments. In some embodiments, controllers can be configured to adjust regimens to achieve predetermined pharmacokinetic and / or pharmacodynamic effects based on pharmacodynamic effects. In some embodiments, controllers are configured to execute predetermined regimens that include the step of delivering at least two predetermined vaporization amounts. In some embodiments, controllers are configured to adjust various operating settings of the inhaler and lung delivery parameters in real time.

[0390] In some embodiments, the system may further include, or communicate with, a user interface device that can be used to input information and data to a controller and / or to display, transmit, or output data and information from the controller. In some embodiments, the user interface includes an output device for providing information to at least one of the following: a subject, a physician, a memory unit, and a remote device (server, display, remote monitoring system / device, etc.). In some embodiments, the user interface device includes a smartphone device. The smartphone may include a touchscreen, microphone, speaker, GPS receiver, accelerometer, thermometer, photodetector, etc.

[0391] In some embodiments, the controller is configured to monitor at least one predetermined pharmacokinetic effect and / or at least one predetermined pharmacodynamic effect based on data received via a user interface device. Therefore, the controller is configured to adjust a predetermined vaporization rate in real time.

[0392] Figure 9 is a schematic diagram of a system comprising an MDI device (also referred to herein as “inhalation device”), a physician interface, and / or a patient interface, according to several embodiments of the present invention.

[0393] In some embodiments, the MDI device 901 is configured to communicate with a physician interface 903 and / or a patient interface 905. In some embodiments, the MDI device 901 is configured to receive input information from one or both of interfaces 903 and / or 905. Additionally or alternatively, the MDI device 901 is configured to transmit output information to one or both of interfaces 903 and / or 907.

[0394] In some embodiments, communication between system components is performed via one or more data transfer means, such as USB connections, cable connections, wireless connections, and / or any preferred wired and / or wireless communication protocols.

[0395] In some embodiments, communication between system components is performed via one or more communication modules, such as the communication module 907 of the MDI device 901, the communication module 909 of the physician interface 903, and / or the communication module 911 of the patient interface 905.

[0396] In some embodiments, the MDI device 901 includes a controller 913 configured to, for example, activate heating of the substance to vaporize the active agent, control the heating profile and / or thermal activation, control the cartridge supply mechanism of the MDI device, read data from the memory 919 of the MDI device 901, and control power consumption and / or other functions. In some embodiments, the controller 913 communicates with the memory 919. If necessary, the memory 919 is configured to store prescription data, personal use data, patient details, individual PD effects obtained from the patient, partial changes in dose and / or regimen, parameters obtained from the patient in response to changes in dose and / or regimen, and / or other numerical values ​​or information. In some embodiments, the controller 913 activates lung delivery of the active agent according to the dose and / or regimen data stored in the memory 919. In some embodiments, the memory 919 is configured to store patient use data and / or feedback data regarding a specific dose and / or regimen, and / or a pre-selected (desired) PD profile of the active agent in the patient.

[0397] In some embodiments, the physician interface 903, which includes, for example, one or more of a controller 915, memory 921, and / or a communication module 909, is configured on a personal computer (tablet computer, laptop computer, desktop computer, etc.), a smartphone, a portable device, a wearable device, a wrist device, or an integrated eyewear device, a clinic or hospital monitor, and / or any other suitable device. If necessary, the physician has means to remotely access the MDI device 901. Additionally or alternatively, the physician can directly activate the MDI device 901. In some embodiments, the physician pre-programs (pre-calibrates or pre-sets) the MDI device 901 with a predetermined vaporization volume (dose and / or regimen) suitable for an individual patient. In some embodiments, data is transmitted from the physician interface 903 to the patient interface 905, for example, to instruct the patient or to perform pre-set adjustments.

[0398] In some embodiments, for example, the patient interface 905, which includes one or more of a controller 917, a memory 923, and / or a communication module 911, is configured on a personal computer (tablet computer, laptop computer, desktop computer, etc.), a mobile device such as a smartphone, and / or on the MDI device 901 itself.

[0399] In some embodiments, the patient interface 905 receives input information 929. The input information may be received from one or more of the patient, the physician interface, the database server, and the MDI device. Examples of various types of input information include: dosage and / or regimen determined by the physician and received by the physician interface; the patient's current individual PD effect written by the patient and / or obtained from the patient; individual usage statistics recorded, for example, on the database server and / or in the memory of the MDI device; a display of inhalation duration and / or inhalation volume sensed by the MDI device; and / or other types of input information.

[0400] In some embodiments, the patient interface 905 includes a display 927. If necessary, the display is an interactive display, such as a smartphone, portable device, wearable device, wrist device, or touchscreen of an integrated eyewear device.

[0401] Depending on the circumstances, certain functions such as data transfer to a physician, access to a database for obtaining user / patient instructions, and / or other functions may be enabled by the patient interface 905, while other functions, such as partial modification of a predetermined vaporization volume (dose) and / or regimen (multiple doses), visualization of other patients' protocols, and / or other functions, may not be available through the patient interface 905. If necessary, the physician sets patient interface access definitions for each individual patient.

[0402] In some embodiments, the patient interface 905 and / or MDI device 901 are configured to notify the patient whenever lung delivery (inhalation) is needed.

[0403] If necessary, notifications are automatically provided based on the planned regimen stored in memory. Additionally or alternatively, notifications can be set by the patient. Additionally or alternatively, notifications can be issued by the physician.

[0404] In some embodiments, one or more system components communicate with the database server 925 by receiving input information from and / or transmitting information to the database. In some embodiments, the database includes individual patient data, such as patient medical history, data transmitted by the MDI device 901, input data from physicians, input data from patients, and / or other information. If necessary, the database server is configured to perform calculations on the data. In some embodiments, the database server 925 includes aggregate data, such as clinical trial results, results from other patients, research data, and / or other data, one or more of the above. If necessary, the database server 925 communicates with multiple treatment systems used by various patients. Data obtained from various interactions between patients and MDI devices is collected in a central database to continuously learn individual patient usage patterns and recommend doses and / or regimens accordingly. By utilizing the collected user database, the creation of accurate predicted doses and / or regimens for current and new patients is improved, and the overall treatment success rate of the treatment is improved.

[0405] In some embodiments, by using the MDI device 901 and / or according to individual feedback data obtained from the patient via the patient interface 905, if, for example, the patient does not use the MDI device when instructed, or / or the MDI device is used at a different time than the pre-set regimen, the predetermined vaporization amount (dose and / or regimen) is automatically corrected by the patient interface controller 917 and / or the MDI device controller 913 to correct improper settings or misuse of the MDI device. Depending on the situation, one or more actions may be taken accordingly, such as postponing the next dose, increasing or decreasing the next dose (and / or subsequent doses), and / or making other regimen changes.

[0406] In some embodiments, patients using the MDI device 901 may wish to plan their dosage and / or regimen to minimize interference with their daily activities due to possible adverse effects. While certain adverse effects may be tolerable at home or at specific times and are acceptable offsets by symptom relief, these adverse effects are undesirable when the patient is engaged in activities such as driving, attending meetings, and / or other activities. If necessary, by using the patient interface 905 and / or by directly activating the MDI device 901, the patient plans their dosage and / or regimen to minimize interference with the activities they plan.

[0407] Additionally, or alternatively, the MDI device 901 and / or patient interface 905 are configured to actively impose specific doses and / or regimens based, for example, on patient input. In one example, the patient writes down the daily activities they plan and the timing of those activities, and the doses and / or regimens are automatically partially modified accordingly. If necessary, the doses and / or regimens are automatically partially modified to ensure that the patient is in a suitable state to perform the planned activities, for example, to ensure that the level of adverse effects during operation is relatively low or imperceptible.

[0408] In some embodiments, the patient may voluntarily partially modify the dose and / or regimen, for example, using the patient interface 905. If necessary, the extent of the partial modification shall be limited to preventing the patient from being at risk, for example, preventing an overdose.

[0409] In some embodiments, the patient can easily use the MDI device 901 even without specific instructions. In such cases, the next dose and / or regimen may be automatically partially modified according to the use. If necessary, the patient is notified of the partial modification of the dose and / or regimen via the patient interface 905. Additionally or alternatively, the physician is notified of such changes, for example, via the physician interface 903.

[0410] Figure 10 is a flowchart illustrating a method for prescribing a regimen to a patient using an MDI device for delivering at least one active agent according to some embodiments of the present invention.

[0411] In some embodiments, a physician may decide to treat a patient by performing pulmonary delivery of one or more active drugs using an MDI device (1001).

[0412] In some embodiments, patient data, such as PK variable elements (e.g., age, sex, BMI, etc.), pathophysiological status, genetic pharmacological and / or pharmacogenetic variable elements and / or other parameters, are written to the system (1003) by, for example, a physician and / or other healthcare professional. If necessary, patient parameters and personal variable elements are written using a physician interface.

[0413] In some embodiments, prescribed doses and / or regimens are created (1005). If necessary, doses and / or regimens are created automatically by, for example, physician interface software. Additionally or alternatively, doses and / or regimens are planned by a physician. In some embodiments, doses and / or regimens are created by adapting written patient data to predetermined doses and / or regimens using data from a database, or according to individual feedback data, or according to, for example, an index table.

[0414] In some embodiments, a simulation of the patient's expected PK / PD profile is performed for the selected dose and / or regimen (1007). In some embodiments, the predicted PK / PD profile, including, for example, therapeutic effects and / or adverse effects, is simulated. In some embodiments, a treatment window is selected based on the correlation between the pharmacodynamic profile and / or pharmacokinetic profile and the patient's personal data. If necessary, the PK / PD profile simulation and / or pre-selected treatment window is displayed to the physician as a graph, for example, on the physician interface display. Taking the simulation into consideration, the physician may decide to make partial modifications to the (personalized) dose and / or regimen to better suit the patient (1009). If necessary, the physician may decide to modify the proposed dose and / or regimen parameters, such as dose, mode of administration, regimen or total treatment time and / or one or more other treatment parameters.

[0415] Depending on the circumstances, treatment may involve administering two or more substances simultaneously or sequentially to obtain a desired therapeutic effect in the patient. According to some embodiments of any of the embodiments of this disclosure, the system enables the use of MDIs that deliver multiple pharmaceutically active agents (derived from one or more substances) in any proportion or predetermined vaporization rate to exhibit a pre-selected PD profile (e.g., to maintain individual patients within a patient-calculated treatment window). In some embodiments, different doses are selectively administered according to a regimen to alleviate symptoms while preventing adverse effects.

[0416] In some embodiments, a selected (and, if necessary, refined) dose and / or regimen is prescribed to the patient (1011).

[0417] In some embodiments, as part of follow-up, over the course of the patient's treatment period (e.g., several hours, a day, a week, a month, and / or in the middle of those periods, or longer or shorter periods), the physician receives one or more indicators, such as indicators of the patient's general use of the device; indicators of one or more of the patient's personal PD effects regarding the presence of adverse effects, such as the dose and / or regimen administered to the patient, the substances consumed by the patient, such as psychoactivity levels; and / or indicators regarding the severity of symptoms, such as pain levels, and / or the levels of one or more biomarkers; and / or other indicators (1013). If necessary, one or more indicators are provided in real time. Additionally or alternatively, indicators are provided at the end of drug delivery to the lungs. Additionally or alternatively, indicators are provided at the physician's request. Additionally or alternatively, the patient decides when to send indicators to the physician.

[0418] In some embodiments, the indicators are transmitted to the physician automatically and / or in response to instructions from the physician and / or patient, via the MDI device and / or the patient interface. If necessary, one or more indicators are stored in a database for future reference.

[0419] In some embodiments, the dose and / or regimen is adjusted or otherwise partially modified based on the provided indicators (1015). If necessary, the partial modification is made in real time. In some embodiments, a particular dose and / or regimen is partially modified in real time as necessary. In some embodiments, the dose and / or regimen is partially modified taking into account the upper and lower limits of the PD effect, which are individually determined for each patient. The upper limit means that the dose and / or regimen is above the region where significant adverse effects exist. The lower limit means that the dose and / or regimen is below the region where the relief of symptoms treated by the delivery of the active agent is insufficient.

[0420] Figures 11A, 11B, 11C, and 11D are schematic diagrams (Figure 11A) and print screens (Figures 11B, 11C, and 11D) of a physician interface for selecting and prescribing doses and / or regimens to patients according to some embodiments of the present invention.

[0421] Figure 11A illustrates a typical display 1107 of the physician interface. In some embodiments, patient data is written by the physician via input 1109.

[0422] In some embodiments, a graphical representation of the predicted and / or pre-selected pharmacokinetic profile 1111 and / or expected and / or pre-selected pharmacodynamic profile 1113 is presented to the physician. If necessary, one or more profiles are shown separately from or together with a time series 1115, such as the duration of treatment (e.g., in one-hour increments) for the patient. In some embodiments, a treatment window 1117 is defined, with upper limits 1119 and lower limits 1121 set.

[0423] In some embodiments, the dose and / or regimen is selected to keep the predicted and / or pre-selected PK / PD profile within the therapeutic window 1117.

[0424] In some embodiments, the limit values ​​are defined as constant values ​​represented by a straight line, for example, as shown in Figure 11A. Alternatively, the limit values ​​may include a variable set of numbers and be represented as a curve. For example, the lower limit 1121 represents the desired therapeutic effect, the upper limit 1119 represents the acceptable adverse effect, and the C value represents a high pharmacokinetic profile. max The threshold may be set, for example, in the early stages of treatment to promote symptom relief, and C maxThe threshold may be lowered as treatment continues, if necessary. In some embodiments, the dose and / or regimen is selected and / or adjusted to achieve, for example, an initial accumulation of the active drug in the patient at the beginning of treatment, and then a continuous dose to maintain the patient in a steady state (maintenance dose). Generally, the initial accumulation of the drug is based on a relatively large amount of the drug compared to the amount given in the maintenance dose.

[0425] In some embodiments, for example, when refining the predetermined vaporization amount (dose and / or regimen) of the drug for individual patients, the physician may perform one or more operations of increasing and / or decreasing the threshold values ​​1119 and / or 1121, increasing and / or decreasing the peaks of profile 1113 and / or profile 1111, extending and / or shortening the treatment period along the time axis, and / or making other partial modifications.

[0426] While the specification shows a graph as an example, please note that various graphs, such as bar graphs, can be used. In some embodiments, profiles 1111 and / or profile 1113 may be presented in a discontinuous manner, for example, as a set of points.

[0427] Figure 11B shows a simulation of a patient's predicted pharmacokinetic profile using a predetermined vaporization rate delivered according to a predetermined regimen according to several embodiments. In this example of a physician interface screen, the physician can fill in patient data 1101 (such as sex, weight, height, administered drugs, patient ID, and / or other data) and also obtain an extrapolation of the individual patient's pharmacokinetic profile, for example, shown in graph 1103 which simulates the plasma concentration of the active drug in the patient over time.

[0428] Similarly, Figure 11C illustrates the extrapolation of the predicted pharmacodynamic profiles of individual patients, showing the level of adverse effects in patients over time.

[0429] Figure 11D shows a screenshot of a physician interface according to several embodiments of the present invention. The simulated pharmacokinetic profile is represented in Graph 1103, and the simulated pharmacokinetic profile is represented in Graph 1105, both displayed on a time series axis 1115, representing 8 hours in this example. The patient's pharmacokinetic parameter scale is visually divided into several segments, each defined for each individual patient, for example, representing a "painful" state (below the therapeutic effect level), an "optimal" state (within the therapeutic window), and a "psychoactive" state (above the adverse effect level), and the simulated PK / PD profile as a graph is shown in relation to these segments. In this simulation, the first dose is administered at 8:00, and both the pharmacokinetic and pharmacokinetic parameters change, rising from the "painful" segment to the "optimal" segment. The second dose administered at 11:00 is seen to maintain the patient in the "optimal" (therapeutic window) state.

[0430] Figure 12 is a flowchart illustrating a method for obtaining patient feedback and accordingly partially modifying / adjusting the dosage and / or regimen, according to several embodiments of the present invention.

[0431] In some embodiments, the PD effect can be obtained for individual patients (1201).

[0432] In some embodiments, the PD effect is related to adverse effects such as psychoactivity levels, therapeutic effects such as pain levels, and / or changes in any of these levels. Examples of the PD effect include the absolute quantification and / or relative quantification of levels assessed for levels measured before the delivery of a single dose and / or before the delivery of the dosage and / or regimen. The PD effect may also be obtained before, during, and / or after the delivery of a single dose, and / or before, during, and / or after the delivery of the dosage and / or regimen, and / or before, during, and / or after the entire period in which the treatment is provided to the patient.

[0433] In some embodiments, the PD effect is provided directly by the patient, for example, using a patient interface. In some embodiments, the patient can manually adjust the visual representation of the PD effect based on their personal determination of the level of the PD effect. In one example, the patient may move a bar on a graph displaying the pain level up or down on a touchscreen of, for example, a mobile phone and / or other personal device in which the patient interface is configured.

[0434] In some embodiments, patients who are unable to effectively summarize the level of PD effects may utilize an interactive toolset to assist in determining the current level of PD effects, such as those further described herein.

[0435] In addition to, or instead of, the conscious and personally perceived PD effects exhibited by the patient, individual PD effects such as biomarkers can be obtained by the patient interface and / or system, for example, using sensors. In some embodiments, one or more standard components of a mobile phone and / or personal computer that constitutes the patient interface act as sensors for acquiring parameters. Some components that can be used as sensors to obtain PD effects from a patient include: a touchscreen can be used, for example, to assess dexterity, eye-hand coordination, and / or memory and cognitive states; gesture sensors such as gyroscopes, accelerometers, proximity sensors, and / or IR sensors can be used, for example, to assess motor skills; a camera and / or light source can be used, for example, to detect visual tracking, intermittent motion changes, ocular vasodilation, pupil dilation, and / or pulsation; RGB lighting can be used, for example, to assess environmental perception; a magnetometer and / or GPS can be used, for example, to assess direction; a speaker and / or microphone can be used, for example, to assess hearing and / or vocalization skills; and a temperature and / or humidity sensor can be used, for example, to assess body temperature.

[0436] In some embodiments, the MDI device is configured to acquire individual feedback data. In one example, the MDI device includes a flow sensor and / or a pressure sensor.

[0437] If necessary, patient respiratory-related indicators are obtained using flow and / or pressure sensors. In some embodiments, the sensors are adapted to detect inhalation volume. In some embodiments, since a correlation may exist between inhalation volume and PD effects such as pain level, flow and / or pressure measurements are initiated to determine the PD effect in the patient.

[0438] Once a PD effect for one or more individuals is obtained, the dose and / or regimen may be partially modified accordingly (1203). In some embodiments, the dose and / or regimen is partially modified to improve or otherwise modify the patient's condition based on a provided indicator, on the one hand, and to pre-select a pharmacodynamic profile, such as maintaining the patient within a treatment window between a lower limit of the therapeutic effect that alleviates symptoms and an upper limit of the adverse effect that is still significant, on the other hand. In some embodiments, the MDI device can be configured such that patient input increases the dose and / or adjusts the frequency and / or amount of the regimen when the therapeutic effect falls below a minimum. If necessary, the dose and / or regimen is partially modified to obtain a level that exceeds the minimum therapeutic effect. Additionally or alternatively, the dose and / or regimen is partially modified to the same extent that the maximum level of adverse effect is acceptable.

[0439] Figures 13A, 13B, 13C, 13D, and 13E are screenshots of patient interfaces (Figures 13A, 13C, and 13E) according to several embodiments of the present invention, and graphical representations of the patient's predicted pharmacodynamic and pharmacokinetic profiles before and after input of the patient's individual PD effect.

[0440] Figure 13B shows an example of a 3-hour regimen calculated for a specific patient (Patient X, 35 years old, BMI 22). According to this example of a calculated regimen, in order to maintain Patient X within a 3-hour treatment window and bring about the PK profile represented by the red curve in Figure 13B, Patient X needs to be subjected to pulmonary delivery of the active agent using a quantitative MDI device according to some embodiments of this disclosure at the following times and doses: 00 min - 1.2 mg; 10 min - 1.0 mg; 60 min - 0.5 mg. The blue curve represents an example of a PD profile calculated at the indicated doses. As shown in the figure, the calculated regimen maintains Patient X within a treatment window 1303 that is below the limiting level, i.e., the adverse effect level, and within the therapeutic effect level, i.e., in the range of 2.5 to 7.5 on the harmful psychoactive effect scale.

[0441] In Figure 13C, during and / or after treatment, patient X indicates a desire to change the adverse effect limit, for example, by raising the psychoactive level bar 1301 on the patient interface screen. Raising the bar indicates that the patient desires to increase the tolerable level of adverse psychoactive effects. As shown in Figure 13D, the treatment window is then redefined based on the patient's input—for example, by narrowing the window to a range of 2.5 to 5 on the psychoactive scale. The dose and / or regimen administered at this point may then be partially modified accordingly. For example, a predetermined vaporization volume planned for, say, the 60-minute lung delivery from the first lung delivery is reduced to 0.5 mg to 0.3 mg to lower the level of adverse effects (psychoactive effects) the patient is experiencing.

[0442] In some embodiments, the dosage and / or regimen is automatically partially modified based on patient input. Additionally, or alternatively, patient input and / or simulated profiles are automatically and / or, at the patient's request, forwarded to the physician, who then partially modifies the regimen.

[0443] It should be noted that a patient's sensitivity to therapeutic effects and / or adverse effects may vary throughout the day in a single patient. For example, it has been shown that pain sensitivity increases at night and cognitive function declines in the morning, and therefore sensitivity to therapeutic effects is lower at night or higher in the morning.

[0444] In addition to or instead of the level of adverse effects, patients may also indicate their level of therapeutic effect and / or other conditions, to which the dosage and / or regimen may be partially modified accordingly.

[0445] Figure 13E shows a patient interface application comprising an adjustable slider 1305 that can be moved by the patient. In some embodiments, the application presents the patient with an assessment of their current condition calculated based on one or more of the following: predetermined doses and / or regimens, past input information obtained from the patient such as biomarkers and / or other direct and / or indirect individual PD effects, the individual patient's treatment and effect history, the patient's usage records, the patient's medical status, information from collected databases, and / or other information.

[0446] During and / or after treatment, patients can also drag sliders to reflect their perceived PD profile. For example, when a patient experiences full therapeutic effect (e.g., the patient is no longer in a painful state), they can move the slider to the "optimal" state (e.g., the "psychoactive" state).

[0447] By using input information obtained from the patient, the patient interface can automatically partially modify the next dose and / or regimen. In some embodiments, a partial modification instruction 1307 is displayed to the patient, notifying them, for example, that the next dose will be increased. If necessary, the application is configured to request confirmation 1309 from the patient to modify the dose and / or regimen.

[0448] In some embodiments, patient input and / or partially modified settings are automatically transmitted to the physician interface. In some cases, the physician may decide to manually modify the newly defined dosage and / or regimen settings.

[0449] Figure 14 is a flowchart illustrating a method for measuring one or more biomarkers using a personal portable device and / or MDI device according to some embodiments of the present invention, and for partially modifying the dose and / or regimen accordingly.

[0450] In some embodiments, one or more biomarkers are measured (1401). In some embodiments, the biomarkers indicate the presence and / or degree of adverse effects in the patient being treated. If necessary, the biomarker scale is used to determine the treatment window for individual patients and / or to control the dose and / or regimen to keep the patient within the treatment window.

[0451] Adverse effects such as cognitive impairment and other psychoactive effects may vary among patients with diverse genetic and biological traits. Therefore, in some embodiments, individual biomarkers, such as CNS biomarkers, are obtained from patients using, for example, one or more sensors in a system and / or one or more sensors configured within a patient interface device, such as a mobile phone sensor as described above.

[0452] Non-invasive biomarker assessment methods include one or more of the following: oculoscaponic movement assessment (such as impulsive movements), memory tests, adaptive tracking, finger tapping assessment, posturography assessment, visual analog scale fitting, and / or other assessment methods.

[0453] In some embodiments, various non-invasive biomarker tests known in the art, such as cognitive tasks, are performed. These tests include, for example, reaction time, attention, visuospatial span, name recall, story recall, physiognomy recall, name-face association, construction, verbal fluency, object naming, implicit memory, logical reasoning, and / or other cognitive tasks.

[0454] In some embodiments, biomarker measurements are communicated to a physician (1403). If necessary, PD effect measurements are stored in the memory of the MDI device and / or the patient interface memory. Additionally or alternatively, PD effect measurements are uploaded to a database. If necessary, PD effect measurements are compared with PD effect measurements stored in the database, which may include, for example, past PD effect measurements for the individual patient, PD effect measurements for other patients, PD effect measurements from the literature, etc.

[0455] In some embodiments, the dose and / or regimen is partially modified according to the PD effect measurement (1405).

[0456] Figures 15A, 15B, and 15C are screenshots of a patient interface equipped with various applications for acquiring PD effect data and / or assisting patients in determining the amount of drug vaporized (dose and / or regimen) according to some embodiments of the present invention.

[0457] In applications shown herein as examples that can be installed on personal portable devices such as mobile phones and / or tablet computers, the patient performs one or more tasks interactively, and these tasks may be incorporated as part of gameware, etc., based on the individual PD effect that can be evaluated based on the tasks. In some embodiments, the level of adverse effects, such as the patient's psychoactivity level, is automatically estimated by the application. Additionally or alternatively, the application may assist the patient in effectively summarizing the therapeutic and / or adverse effects perceived by the patient, and these effects can then be provided to the system as input information.

[0458] Tasks described herein include, for example, tracking a target with a finger (Figure 15A), visually tracking a target (Figure 15B), and positioning a target (Figure 15C).

[0459] Other applications include various individual PD effectiveness measurements utilizing activities and methods known in the art, such as simulated driving, card sorting, arithmetic skills testing, time estimation, symbol copying, adaptive tracking, reaction time, drawing and / or speech skills, and / or other applications, as described above.

[0460] Figure 16 is a schematic diagram of a quantitative MDI device configured to automatically deliver one or more active drugs to the lungs according to several embodiments of the present invention.

[0461] In some embodiments, the apparatus 1601 includes a substance dispenser 1603, for example, a dispenser for a substance containing a pharmaceutically active agent, from which the pharmaceutically active agent is vaporized. In some embodiments, the substance dispenser includes, or is in communication with, a mechanism for processing the substance to obtain a deliverable pharmaceutically active agent, for example, a raw material for at least one substance from which the active agent is derived, as described herein above.

[0462] This substance may include various forms, such as solid raw material, solid particles, or powder. If necessary, the substance is contained in a cartridge, capsule, and / or other container. In some embodiments, the processing mechanism may include one or more of the following: heating (e.g., for vaporization), aerosolization, induction of a chemical reaction by mixing with other materials, etc., release of the substance from the container by rupturing a capsule, pressure propulsion, mobilization, and / or other types of processing. Alternatively, the active agent may already be in a ready-to-use form and require no processing before being delivered to the user by heating.

[0463] In some embodiments, the MDI device 1601 includes an input module 1605. Optionally, the input module 1605 is configured to receive data relating to the dose and / or regimen in which the active drug is delivered to the patient. Additionally, or alternatively, the input module 1605 is configured to receive one or more signals from sensors (not shown) provided within and / or configured outside the device 1601.

[0464] In some embodiments, the MDI device 1601 includes a controller 1607 configured to initiate and / or partially modify and / or stop the delivery of a pharmaceutically active drug to the lung. In some embodiments, the controller 1607 operates a substance dispenser 1603 that activates the heating of the substance by, for example, a heating element. In some embodiments, the controller 1607 initiates the delivery of a predetermined vaporized amount of the drug, such as a dose and / or regimen, received as input. In some embodiments, the controller 1607 controls the flow rate of the active drug by, for example, activating one or more valves. In some embodiments, the controller is adapted to release the drug based on the current flow rate.

[0465] In some embodiments, the MDI device 1601 includes an output unit 1609. Optionally, the output unit 1609 is configured as a mouthpiece operated by the patient. Alternatively, relative to the mouthpiece, the output unit 1609 may be configured as an attachment such as a breathing mask, an infant pacifier, and / or other structure suitable for delivering a stream of vapor to the patient.

[0466] In some embodiments, components of the device 1601, such as a substance dispenser and / or a controller and / or other components, are housed within the housing 1611. If necessary, the housing is shaped and sized for use as a portable device.

[0467] In some embodiments, the MDI device 1601 includes a flow control mechanism.

[0468] If necessary, the vapor flow rate is controlled using one or more valves. In some embodiments, the flow rate is selected and / or partially modified for each individual patient, for example, by a sensor incorporated into the MDI device, instructing the user to time the delivery and ensure that the active agent flows to the patient only while they are inhaling. In some embodiments, the device is configured to partially modify the flow rate so that the patient can intuitively identify when to stop inhaling, when to inhale more deeply, and / or when to change the breathing rhythm and / or intensity. In one example, the device delivers pulses of increased flow rate to instruct the patient to stop inhaling.

[0469] In some embodiments, the flow rate is selected and / or partially modified to reduce the amount of active drug trapped in the outflow duct of the device and not delivered to the patient. In some cases, the amount of trapped active drug is reduced to a known predetermined amount by controlling the flow rate.

[0470] In some embodiments, the flow rate is controlled by the controller 1607. If necessary, the flow velocity is controlled according to data received by the input module 1605, data acquired by sensors, and / or other instructions.

[0471] Potential advantages of a device equipped with a flow control mechanism operable for each individual patient include improved accuracy of delivery to the patient in terms of timing and / or the predetermined vaporization amount of the active agent delivered by the device, and improved performance of the system / MDI device.

[0472] Figure 17A is a schematic diagram of the configuration of an MDI device 1701 according to several embodiments of the present invention.

[0473] In this configuration, the substance dispenser 1703 comprises a substance cartridge 1705, a heating element 1707, and a feeder 1709 that moves the substance cartridge relative to the heating element 1707, for example, to contact or be close to the heating element.

[0474] In some embodiments, the heating element is configured to provide local heating, for example, by conduction, convection, and / or radiation. In some embodiments, the material is heated sufficiently and rapidly to a temperature suitable for forming vapor of volatile pharmaceutically active agents contained therein. In some embodiments, the material is constructed as a movable element that can be selectively and / or locally activated. If necessary, the material is constructed in a compressible form. If necessary, each form represents a predetermined vaporization amount.

[0475] In some embodiments, vapors released from a substance collect in a vapor chamber 1711 and then travel from there to the patient via an outlet pipe.

[0476] If necessary, valve 1713 is placed along the pipe to control the flow velocity.

[0477] In some embodiments, the device 1701 includes a mouthpiece 1715 that delivers vapor to the patient in response to inhalation. Alternatively, the mouthpiece 1715 can be attached to other elements, such as an oxygenated mask and / or nasal cannula, if necessary, for delivery therapy to, for example, a debilitated patient. If necessary, the mouthpiece is in fluid communication with a valve 1713.

[0478] In some embodiments, the device 1701 includes a power supply 1717, such as a battery, a manual winding spring, and / or a wall socket plug.

[0479] In some embodiments, the device 1701 includes, for example, a controller 1719 as described herein, which is configured to control one or more of the valve 1713, the power supply 1717 and / or the substance dispenser 1703 as a whole, and / or to control the components of the substance dispenser separately. In some embodiments, the controller 1719 verifies that the substance cartridge is permitted for use.

[0480] In some embodiments, the controller 1719 communicates with a memory 1721 that can be read from and / or written to by the controller.

[0481] Figure 17B shows a cartridge 1723 comprising a plurality of individual substance cartridges 1725. Each cartridge 1725 contains one or more substances 1727 (plant-based materials) for vaporization, sealed within a heating element 1729 that serves as the cartridge housing. In some embodiments, the heating element 1729 takes the form of a wire cage-like net surrounding the substances. In some embodiments, an electric current is passed through the heating element 1729 to heat the substances contained in specific individual cartridges in order to vaporize the active agent.

[0482] According to some embodiments, the system provided herein comprises at least one dose unit containing an active drug-containing plant material. In some embodiments, the system comprises multiple dose units, and the controller is configured to use at least one of the dose units to vaporize the active substance from the dose units.

[0483] In some embodiments, the system comprises multiple dose units, each containing a plant material having at least one pharmacologically active agent of a different composition. In some embodiments, a subset of dose units has essentially the same active agent (one or more) composition. In some embodiments, multiple dose units have the same agent but in different ratios. According to some embodiments, the system's controller is configured to select at least one dose unit based on its active agent composition. For example, the controller can be used to select a dose unit containing a plant material with one active agent, and then another dose unit to vaporize a different active agent. It is also possible to use the controller to perform different heating temperatures at different times to vaporize different agents from the same dose unit based on various vaporization temperatures. In some embodiments, the controller is configured to select a series of dose units having the same or different compositions for inhalation, either at the same time or immediately afterward, thereby providing a combination of agents and / or a larger quantity than can be delivered by a single dose unit.

[0484] Here, refer to Figures 17C-D, which are schematic diagrams of the dosage unit 2300 (vaporizing cartridge for administered substance) that have been disassembled and assembled according to several embodiments.

[0485] Figures 17C-D are schematic diagrams of dose units (vaporizing agent cartridges, or cartridges) according to several embodiments, showing a dose unit 2300 (Figure 17C) that houses a substance 2304 containing one or more active agents and fits into an opening 2303 of a frame 2308 that forms part of a housing 2301, and a resistance heating element 2306 (Figure 17D) that is in thermal contact with two opposing surfaces of the substance 2304 and extends across those opposing surfaces. In some embodiments, the resistance heating element 2306 extends across only one surface of the substance 2304, but in other embodiments it extends across more than two opposing surfaces.

[0486] In some embodiments, a predetermined or known amount of a substance containing one or more active agents is assembled on and / or inside the dose unit 2300. If necessary, the dose unit 2300 is: If necessary, for rapid vaporization, for example, a substance 2304 formed by planarization; Mechanical support for material 2304 (e.g., support by encapsulation within the opening 2303 of the frame 2308 of a housing 2301, which may be frame-shaped as needed); Means for facilitating the transport of the dosage unit 2300 (e.g., a latch mandible 2302); and / or The system includes means for heating (vaporizing) the substance 2304 (e.g., a resistance heating element 2306, e.g., a mesh).

[0487] If necessary, at least a portion of the dosage unit 2300 containing at least a portion of substance 2304 (or at least the entire heated portion of substance 2304) is air permeable, thereby allowing air to pass through the substance during heating and carry a thermal vaporizer to the substance.

[0488] Where necessary, the dose units are disposable. Potential advantages of disposable dose units include: containment of disposable active drug residues; close integration of dose support and transport to ensure reliable drug transport within the dispensing device; and / or reduced need to maintain and / or monitor parts of the drug delivery system (such as vapor heating elements) that may be subjected to conditions that could degrade performance over time.

[0489] Where necessary, the dose unit is intended for single-inhalation use. Potential advantages of single-use dose units include improved precision and / or reliability in controlling the amount of bioactive agent vaporized under inhaler settings. For example, the concentration and / or dispersion of the active agent in substance 2304 can be controlled to a certain degree of precision during manufacturing. Generally, the degree of variation in the device's output (e.g., the amount of active agent vaporized and inhaled) can be kept within a tolerable range of less than ±15% of the intended output. Other factors that may affect the variation in the device's output include ambient conditions, user habits, and the user's current condition.

[0490] In some embodiments, the dosage unit 2300 comprises a housing 2301 having an opening or a receiving chamber 2303. Optionally, the housing 2301 comprises a flat, elongated strip, and the receiving chamber 2303 comprises an opening formed by the strip (frame 2308). During the preparation of the dosage unit 2300, a substance 2304 is inserted into the receiving chamber 2303. Optionally, the substance is shaped to conform to the receiving chamber 2303 before or during insertion, so as to match the flat shape of the receiving chamber 2303. It may be advantageous to hold the substance 2304 in a flat form, as a larger surface area and / or uniform thickness allows for faster and / or more evenly distributed heating and / or airflow during vaporization and delivery.

[0491] In some embodiments, the dimensions of material 2304 are, for example, approximately 6 × 10 mm across the entire exposed surface area, with a thickness of approximately 1 mm. If necessary, the thickness of material 2304 is in the range of approximately 0.1 to 1.0 mm, or thicker, thinner, or intermediate in thickness. If necessary, the surface area of ​​material 2304 is approximately 20 to 100 mm². 2 For example, 20mm 2 , 40mm 2 , 50mm 2 , 60mm 2 , 80mm 2The surface area is within the range of, or wider than, narrower than, or intermediate between these ranges. The substance 2304 is formed, if necessary, into a square or nearly square shape (e.g., about 8 × 8 × 1 mm); if necessary, the substance 2304 is a rectangle with a side ratio of, for example, 1:2, 1:3, 1:4, 1:10, or greater than, smaller than, or intermediate between these side ratios. If necessary, the dimensions of the substance 2304 are, for example, about 30 × 2 × 0.5 mm. In some embodiments, the weight of the substance 2304 corresponding to that shape is about 15 mg. In some embodiments, the weight of the substance 2304 is selected from a range of about 1 to 100 mg, or another range including that range, heavier, lighter, and / or intermediate ranges.

[0492] Enclosing material 2304 in a framing enclosure 2301 may be advantageous in order to enhance mechanical stability. For example, material 2304 potentially contains individual material particles, and therefore material 2304 is particularly prone to particle leakage when moved or bent. By sealing it within a cartridge frame 2308, material 2304 can move within the system without directly applying stress to it. In some embodiments, the overall length and width of the cartridge are approximately 20 × 10 mm, or longer, shorter, or intermediate in size. During manufacturing, a framing enclosure may be advantageous in forming a material sample of the correct dimensions for fitting and blocking airflow conduits to capture volatile substances released during heating of the material.

[0493] In some embodiments, vaporization of the active agent involves heating by a resistive heating element 2306 or other forms of resistive heating elements. The resistive mesh is made of a material that exhibits sufficient resistive heating as needed; for example, nichrome (typical resistivity about 1–1.5 μΩ·m), FeCrAl (typical low resistivity about 1.45 μΩ·m), stainless steel (typical resistivity about 10–100 μΩ·m), and / or cupronickel (typical resistivity about 19–50 μΩ·m). Depending on the choice of material (e.g., metal), parameters such as the length and width of the heating element, thickness, opening dimensions and / or opening pattern are adjusted so that the total resistance across the entire resistive heating element is, for example, in the range of about 0.05–1 Ω, 0.5–2 Ω, 0.1–3 Ω, 2–4 Ω, or another range including, higher than, lower than, and / or intermediate ranges.

[0494] If necessary, during assembly, the resistance heating element 2306 is mounted to the housing 2301 in a position that covers the material 2304 on one or more sides. For example, the resistance heating element 2306 is U-shaped, extending from the dorsal surface 2309A to both sides of the frame 2308, folding around the housing end 2311, and extending rearward along the ventral surface 2309B. If necessary, the resistance heating element 2306 extends around the chamber 2303 so that the material 2304 contained within the chamber 2303 is surrounded by the heating element 2306. In some embodiments, the resistance heating element 2306 (e.g., mesh) comprises multiple separate panels, for example, one panel on each side of a cartridge. If necessary, the multiple panels are electrically connected to each other. A possible advantage of double-sided mesh encapsulation of material 2304 is the increased rate and / or uniformity of vaporization when current is applied to the heating element 2306. In some embodiments, the heating element is embedded entirely or partially within the material 2304. If necessary, the heating element is partially or entirely embedded within the frame 2308 of the housing 2301; for example, the housing 2301 is molded integrally with the heating element 2306 from the outset, and / or the heating element 2306 is press-molded in place at a high temperature during another manufacturing stage.

[0495] In some embodiments, the ratio of the open portion (aperture) to the closed portion (mesh material) surface area of ​​the resistance heating element 2306 is between approximately 1:1 (50%) and 1:3 (33%). In some embodiments, this ratio is in the range of approximately 10–20%, approximately 20–40%, approximately 30–50%, approximately 40–70%, approximately 60–80%, approximately 70–90%, or a range of ratios including these ranges, higher, lower, and / or intermediate ranges. In some embodiments, the holes in the mesh are in the range of approximately 10 μm, approximately 25 μm, 32 μm, 50 μm, 75 μm, 100 μm, 200 μm, 300–750 μm, 700–1200 μm, or higher, lower, or intermediate ranges. If necessary, the dimensions and / or shapes of at least two openings are different. In some embodiments, the mesh is 400 / 0.03 316 stainless steel mesh, having 400 0.033 mm holes per square inch, with each hole being approximately 0.033 mm (33 μm) in diameter and having a thickness of 0.03 mm.

[0496] In some embodiments, the resistive heating element 2306 consists of an etched resistive foil (e.g., foil etched into a continuous ribbon or other shape and backed with a polymer such as polyimide and / or silicone rubber). If necessary, the backed resistive foil is perforated through the backing to allow air to flow during the vaporization of the administered substance. In some embodiments, a fuse is added to the resistive foil, for example as an additional component and / or a deliberately thinned area of ​​ribbon, to provide a method for destroying the heating element after use (by supplying a moderately high current to the heating element for a sufficient amount of time).

[0497] In some embodiments, the resistance heating element 2306 is fixed to the cartridge housing 2301 by press-molding the mesh into the housing using a temperature high enough to melt and / or soften the housing so that the mesh is embedded in the housing material. In some embodiments, the housing is made of an inert, heat-resistant, non-conductive material. In some embodiments, the housing material used includes, for example, liquid crystal polymer (LCP), polyetheretherketone (PEEK), Ultem, Teflon, Torlon, Amodel, Ryton, Forton, Xydear, Radel, Udel, polypropylene, Propylux, polysulfone, or other polymer materials.

[0498] A potential advantage of LCP and / or PEEK is their good resistance to temperatures higher than the temperature required to vaporize the material held in the cartridge. In some embodiments, the mesh and housing are joined at a temperature of about 280°C (or another temperature high enough to melt and / or soften the LCP or PEEK). LCP and PEEK may offer the advantage of exhibiting good thermal stability at lower temperatures, for example, vaporization temperatures of about 230°C.

[0499] A possible advantage of providing a heating element, such as a resistive heating element 2306, for each individual dose unit is that performance will be more uniform between uses. Some of the bioactive agent that the heating element comes into contact with may remain on the heating element after cooling. This accumulation may affect vaporization performance. Remote heating (e.g., by radiation and / or indirect conductance) may produce systems with relatively high thermal inertia (requiring greater heating power) compared to direct conductive heating by contact electrodes; the problem of contact electrode contamination can be eliminated by designing for single use. Reduced heating needs may improve safety and / or device lifespan. Reduced heating needs also reduce power supply requirements, which may improve portability, extend battery life, and / or reduce costs (e.g., in systems with battery-powered heating elements).

[0500] In some embodiments, the dosage unit 2300 (cartridge) includes a locking member for use in transporting the cartridge. The locking member includes, for example, a jaw latch 2302. The locking allows engagement by one or more fitting members of the dosing system transport mechanism for fixing and / or moving the cartridge. During the cartridge lifecycle, for example: when placing the cartridge in a row of cartridges including multiple cartridges arranged for use, when the cartridge moves forward in the row, when selecting a cartridge for use, when moving the cartridge to the use position, when actually using the cartridge, and / or when the cartridge is discarded or when moving the cartridge to the “used” position in the row of cartridges, the cartridge is moved and / or secured against unnecessary movement.

[0501] The generated steam is collected in a steam chamber as needed and delivered to the patient.

[0502] A potential advantage of individually heated cartridges is, for example, the ability to more precisely control the predetermined vaporization amount of active drug delivered to the patient compared to a movable strip of a cartridge heated by a fixed heating element. Loading and heating specific cartridges individually at specific times may improve the accuracy of the MDI device.

[0503] Figure 18 is a flowchart of a method for treating individual patients using the system shown in Figure 9 while maintaining the patient within a treatment window according to several embodiments of the present invention.

[0504] In some embodiments, the MDI device is programmed with a predetermined vaporization volume (dose and / or regimen) (1801). If necessary, the dose and / or regimen is set in the inhaler by the physician manually (e.g., by activating a button on the device itself) and / or using the physician interface. Additionally, or alternatively, the dose and / or regimen is set in the MDI device according to instructions transmitted from the patient interface.

[0505] In some embodiments, the MDI device is configured to select at least one predetermined vaporization amount for inhalation sessions involving multiple inhalations based on the contents of a dose unit, as needed, and to control the predetermined vaporization amount of the active agent provided to the user by controlling at least one of the heating and airflow within the device. In other words, based on the characteristics of the substance filled in the dose unit, i.e., the amount of active agent(s) available in the unit for vaporization, the device can be configured to vaporize some or all of the available active agent(s) in the substance in one or more inhalations. Here, the controllability of the vaporization amount in each inhalation is provided by controlling the heating level and duration, as well as the airflow rate and duration within the device.

[0506] In some embodiments, the MDI device is activated and the active drug is delivered to the patient (1803). In some embodiments, direct and / or indirect feedback data from the patient is obtained in real time (1805). If necessary, feedback data is obtained during lung delivery (inhalation session). The procedure may typically begin with lung delivery and then end 5 to 20 minutes later, for example, when the pre-selected pharmacodynamic profile for the active drug has fully manifested, and / or at a later point. Additionally or alternatively, feedback data may be obtained over a series of lung deliveries, for example, over periods of 1 hour, 3 hours, 5 hours, 9 hours, 12 hours, or intermediate periods, longer or shorter periods. The protocol may include 5 to 10 lung deliveries per day at time intervals ranging from 15 to 180 minutes between consecutive lung deliveries.

[0507] In some embodiments, the feedback data obtained from the patient includes individual PD effects such as treatment effectiveness, e.g., the severity of symptoms, and / or adverse effects, e.g., the patient's psychoactive state.

[0508] In some embodiments, the patient interface interacts with the patient and obtains feedback data. In some embodiments, questions about the patient's current condition are displayed on the screen for the patient to answer. Such questions may be displayed, for example, in the form of a bar indicating pain levels that the patient moves up or down. Additionally or alternatively, feedback data is obtained by one or more applications, such as gameware, with which the patient interacts. If necessary, non-invasive biomarker levels are estimated by analyzing the patient's input when interacting with the user interface. Additionally or alternatively, feedback data from the patient is obtained by measuring various biomarkers using one or more sensors, for example, by utilizing components of a smartphone, portable device, wearable device, wrist device, or integrated eyewear device that act as a non-invasive biomarker sensor.

[0509] In some embodiments, the individual PD effect is obtained periodically, for example every half day, daily, weekly, or monthly, whenever a need arises, such as before a single dose and / or a series of doses, before and / or after changes in dosage and / or regimen.

[0510] In some embodiments, the dose and / or regimen is partially modified in response to the PD effect (1809). If necessary, the dose and / or regimen is partially modified to achieve the desired effect while keeping the patient within the treatment window, for example, to reduce the patient's pain level. In some embodiments, the dose and / or regimen is repeatedly partially modified by the patient interface. Partial modifications may be made multiple times, for example, during one or more lung deliveries, between deliveries, or after deliveries, and / or over the entire treatment period (days, weeks, months, years) in which the patient is treated. Partial modifications are limited by safety cutoff values, such as doses that could endanger the patient.

[0511] In some embodiments, the patient interface and / or MDI device reminds the patient to perform one or more lung deliveries (1811). Such reminders may be provided as visual signals (e.g., light displays), sounds, vibrations, notifications on portable / handheld devices such as smartphones, handheld devices, wearable devices, wrist devices or integrated eyewear devices, or a combination thereof.

[0512] In some embodiments, patient usage data is recorded and stored in the MDI device memory and / or patient interface memory. If necessary, the delivery of the active drug may be partially modified in real time according to the usage data. For example, if a patient misses one or more lung deliveries, the dose and / or regimen may be automatically partially modified to set up delivery, for example, by increasing the amount of the active drug in one or more subsequent lung deliveries.

[0513] In some embodiments, one or more of the operations described in 1801-1811 may be repeated. Conveniently, repeated acquisition of individual PD effect and / or use data from patients allows for continuous adjustment of dose and / or regimen, providing patients with flexible, precise, and accurate personalized treatment based on the actual therapeutic effects for each individual patient.

[0514] The dimensions and values ​​disclosed herein should not be understood as strictly limited to the exact numerical values ​​listed. Instead, unless otherwise specified, each such dimension is intended to mean both the listed value and a functionally equivalent range before and after that value. For example, a dimension disclosed as "10 μm" is intended to mean "approximately 10 μm".

[0515] As used herein, numerical ranges beginning with the term "about" should not be considered to be limited to the listed ranges. Rather, numerical ranges beginning with the term "about" should be understood to include the ranges accepted by those skilled in the art for all given elements in a microcapsule or formulation in accordance with this disclosure.

[0516] As used herein, the term “about” means within a tolerance range for a particular value as determined by a person skilled in the art, which in part depends on how the value is measured or determined, i.e., the limits of the measuring system. For example, “about” could mean a range of up to 10%, more preferably up to 5%, and even more preferably up to 1% of a given value. Where a particular value is described in this application and claims, unless otherwise specified, the meaning of the term “about” is within a tolerance range for that particular value.

[0517] The terms "comprises," "comprising," "includes," "including," "having," and combinations thereof all mean "to include, but not limited to."

[0518] The term "consisting of" means "to include and be limited to."

[0519] The term "basically consists of" means that the composition, method, or microcapsule includes additional components, processes, and / or parts, provided that such additional components, processes, and / or parts do not substantially alter the basic and novel features of the claimed composition, method, or structure.

[0520] As used herein, the singular forms "a," "an," and "the" include multiple references unless the context specifically indicates otherwise. For example, the terms "compound" or "at least one compound" may include multiple compounds, including mixtures thereof.

[0521] As used herein, the term “method” means, but is not limited to, modes, means, techniques and procedures known to practitioners in the fields of chemistry, pharmacology, biology, biochemistry and medicine, or modes, means, techniques and procedures already developed by such practitioners from known modes, means, techniques and procedures, for achieving a given task.

[0522] Naturally, certain features of the invention described in the context of individual embodiments for clarity may be provided in combination in a single embodiment. Conversely, various features of the invention described in the context of a single embodiment for brevity may be provided separately, in any suitable partial combination, or as suitable for any other described embodiment of the invention. Certain features described in the context of various embodiments should not be considered essential features of the embodiment if the embodiment can operate without those elements.

[0523] The various embodiments and aspects of this disclosure described in detail above and claimed in the following claims section are experimentally supported in the following examples. [Examples]

[0524] Next, the following examples will describe some embodiments of the present invention in a non-limiting manner, along with the above description.

[0525] Example 1 Pharmacokinetic studies A solid substance (cannabis-derived plant material) is heated to produce a predetermined vaporized amount of active agent Δ 9 - Regarding the use of portable quantitative MDI devices configured to deliver THC to the lungs, Δ during the absorption phase 9 - Tests were conducted to characterize inter-individual variability in THC plasma levels.

[0526] Using this study, we will monitor adverse effects, blood pressure, and heart rate, and assess satisfaction on a 0-10 scale using a 10cm Visual Analog Scale (VAS) pain scale (0 = no pain; 10 = most likely severe pain) to measure Δ pain reduction from baseline. 9 - The pharmacodynamic effects of THC delivery to the lungs were further evaluated.

[0527] Study cohort: The trial was conducted at the Pain Research Unit of Rambam Health Care Campus in Haifa, Israel. Cohort patients were enrolled in the trial after meeting the following criteria: (a) 18 years of age or older (b) Having suffered from some form of neuropathic pain for at least three months (c) A stable pain relief regimen of at least 60 days including medical cannabis (d) Normal liver function (defined as aspartate aminotransferase levels less than 3 times the normal level), normal kidney function (defined as serum creatinine levels lower than 133 μmol / L), and normal hematocrit (greater than 38%). (e) If applicable, a negative pregnancy test (determined by a β-human chorionic gonadotropin pregnancy test). (f) Possession of a valid authorization from the Israeli Ministry of Health for the use of medical cannabis.

[0528] The exclusion criteria were the presence of severe heart or lung disease, a history of mental disorder, pregnancy or breastfeeding, or the presence of non-neuropathic pain.

[0529] PK / PD test protocol: The PK / PD trial was conducted using a single-dose, open-label protocol. All patients' medical histories were assessed, and the study physician physically examined each patient. Regular medication was continued throughout the trial. Patients were required to refrain from cannabis use for 12 hours prior to the trial.

[0530] After three successful demonstration pulmonary delivery trials, participants inhaled a single vaporized dose of 15.1 ± 0.1 mg of cannabis flower for approximately 3 seconds.

[0531] Δ 9 - THC and its active metabolite 11-hydroxyΔ 9To monitor plasma levels of THC (11-OH-THC), blood samples were collected immediately before inhalation and at 1, 2, 3, 4, 5, 15, 30, 60, 90, and 120 minutes after inhalation. Whole blood was collected in 13 × 75 mm purple-top Vacutainer® tubes containing EDTA. Samples were kept on ice and centrifuged within 30 minutes. Plasma was divided equally into multiple 3.6 ml polypropylene Nunc cryotubes (Thomas Scientific), frozen at -20°C, and analyzed within 6 weeks. Plasma cannabinoid concentration analysis was performed by multidimensional gas chromatography / mass spectrometry at NMS Labs (Willow Grove, Pennsylvania, USA).

[0532] At baseline (before inhalation) and 20 and 90 minutes after lung delivery of the cannabis-derived pharmaceutical active agent, participants were asked to indicate their current pain intensity on a 100 mm visual analog scale (VAS) ranging from 0 (no pain) to 100 (most likely severe pain), thereby assessing the therapeutic effect of pain reduction. Adverse effects in the form of psychoactive symptoms were recorded at 5, 15, 30, 60, and 120 minutes after lung delivery, along with effects voluntarily reported by participants. Adverse effects were evaluated according to standardized criteria for severity, frequency, duration, and association with the test active agent. Adverse effects were graded using the NIH Division of AIDS table to score the severity of adverse experiences in adults. Blood pressure and pulse rate were also recorded before, during, and after lung delivery.

[0533] Satisfaction with the experience of vapor lung delivery was evaluated using a 100mm VAS ruler, with "None" as the baseline at 0 minutes after treatment and "Very Satisfied" at 100 and 120 minutes after treatment.

[0534] PK / PD test drugs: The crude substance used was 19.9% ​​dronabinol (Δ 9The crude material was pharmaceutical-grade cannabis flower (Bedrocan BV, Netherlands, Veendam) containing THC, 0.1% cannabidiol (CBD), and 0.2% cannabinol (CBN). The crude material was free of pesticides and heavy metals (less than 0.2 ppm lead, less than 0.02 ppm mercury, less than 0.02 ppm cadmium). Foreign matter (stem, insects, and other pests) was removed from the crude material. Microbiological purity was confirmed (total aerobic microorganism count was less than 10 CFU / gram, total yeast and mold count was less than 10 CFU / gram, and Pseudomonas aeruginosa, Staphylococcus aureus, and bile-resistant Gram-negative bacteria were absent).

[0535] The cannabis flower material was lightly ground while retaining all compounds in their unprocessed form, resulting in an activity level of 20.4% Δ 9 - A physically modified substance containing THC was produced. The crushed cannabis was placed in several pre-loaded cartridges, each containing 15.1 ± 0.1 mg.

[0536] MDI device: The MDI device used in this study was a battery-operated, palm-sized, portable quantitative MDI (Syqe MDI®) designed to vaporize multiple doses of a single or more volatile active agent, thereby delivering the volatile active agent to the lungs (see background art, Figure 1, and Patent Document 1). The MDI consisted of a multi-cartridge DAISY, a cartridge counter, an indicator light, and a power switch. Each cartridge was pre-loaded with 15.1 ± 0.1 mg of the substance (cannabis flower) prepared and weighed as described above, and each cartridge contained approximately 3.08 ± 0.02 mg of Δ based on substance analysis. 9- Contained THC. The vaporization and pulmonary delivery process was instantaneously induced by the patient's inhalation force and lasted for approximately 3 seconds. The transition to the next pulmonary delivery was performed by sliding the dose indicator. Each cartridge was heated to approximately 190°C in approximately 470 ms and maintained for exactly 2530 ms. The efficiency of the THC vaporization process was 52.7 ± 2.7% (data not shown), which indicates low variability between pulmonary delivery doses. When linked with real-time flow control and an automated anatomical dead space elimination mechanism, the device allowed inhalation in the range of 1 to 30 L / min, ensuring that all vapor passed through the trachea after inhalation.

[0537] The device minimized the training required from the user. It electronically controlled and recorded the entire lung delivery process, enabling the storage and uploading of treatment data logs. The MDI device further enabled "single-dose" analysis and immediate administration, requiring no pre-treatment or user intervention other than inhalation.

[0538] Pharmacokinetic parameter data and statistical analysis: Peak THC concentration (C max ), and C max (T max The time to reach ) was obtained directly from experimental data (blood samples). The area under the plasma THC concentration-time curve (AUC) was determined by linear trapezoidal non-compartmental analysis (WinNonlin Pro software version 2.0; Pharsight, Mountain View, California, USA). last / λ z The addition of this makes the AUC infinite (AUC 0→infinity ) was extrapolated as . In the formula, C last and λ z These represent the final measured THC concentration and the final slope (slop) on the Ln scale, respectively. For participants who showed residual plasma THC levels at time zero (C0>0), the AUC is shown. 0→infinity The formula is as follows: AUC 0→infinity =AUC 0→last +C last / λ z -C0 / λ zObtained from, in the formula, C0 / λ z This is the residual AUC obtained from the previous dose [see Non-Patent Document 8].

[0539] Results are reported herein as mean ± 1 standard deviation (±SD). For each measured effect (VAS pain intensity, systolic and diastolic blood pressure, heart rate, and satisfaction score), the mean and 95% confidence interval (CI) at different time points were plotted. Differences in VAS pain intensity and satisfaction scores before and after inhalation were examined using a two-tailed Student's t-test. Blood pressure and heart rate values ​​were compared between different time points using one-way ANOVA. A p-value < 0.05 was considered statistically significant. All statistical analyses were performed using Minitab Statistical Software, version 16.

[0540] Eight patients participated in the study. Patient demographic and baseline characteristics are shown in Table 1.

[0541] [Table 1]

[0542] The participants were predominantly male (62.5%), aged 25–69 years (mean age ± SD = 42 ± 14). Mean body weight and body weight index ± SD were 79 ± 21 kg and 27 ± 6, respectively. All participants suffered from neuropathic pain: four had complex regional pain syndrome (CRPS), two had lumbosacral radiculopathy, one had pelvic neuropathic pain, and one had pain associated with spinal cord injury. The median time from diagnosis of neuropathic pain to participation in the study was 48 months (range: 30–147). All patients inhaled cannabis flowers regularly, two to three times a day by smoking.

[0543] The median monthly dose was 20–30 grams (range: 2–5 grams to a maximum of 30–40 grams).

[0544] Table 2 shows the pharmacokinetic data obtained for Δ 9 -THC following single inhalation of 15.1 ± 0.1 mg of cannabis flower containing 3.08 ± 0.02 mg of Δ 9 -THC, self-administered by 8 adult patients as described herein (see Table 1 above). Inter-individual variability in plasma cannabinoid levels at the time of single inhalation is shown in Figure 2 and Table 2 below.

[0545]

Table 2

[0546] Residual plasma THC in 2 patients exceeded the limit of quantification at baseline. In the remaining 6 patients, THC was first detected in blood samples taken 1 minute after inhalation. The mean plasma C max of THC for the group as a whole was 38 ± 10 ng / ml and was reached at 3 ± 1 minutes. The mean THC-AUC 0→infinity was 607 ± 200 ng·min / ml. Measurable plasma levels of the active metabolite (11-OH-THC) were not monitored within the time frame of blood sampling (0 - 120 minutes). The mean baseline VAS pain intensity was 7.5 ± 1.4. A significant analgesic response was observed 20 minutes after inhalation (a difference of 3.4 points, 95% CI: [2.1, 4.9], P = 0.001). As shown in Figure 3, the VAS values reported at 90 minutes post-dose showed results that were actually identical to baseline.

[0547] Adverse effects were minimal, reversible, and well tolerated. Seven patients (87.5%) experienced mild headache during the first 10 minutes after inhalation, but the effect rapidly subsided thereafter. Three patients recovered completely within 15 minutes, and all others recovered within 30 minutes after inhalation.

[0548] As shown in Figure 4, it was observed that compared with the baseline, a significant decrease in mean systolic blood pressure (BP) close to the borderline was shown 30 minutes after 90 minutes of continuous inhalation (133 ± 13 to 122 ± 10 and 121 ± 11 mmHg at 30 minutes and 90 minutes after inhalation, respectively; P = 0.068). During the test period, no significant differences were measured in mean diastolic blood pressure and heart rate (diastolic BP: 82 ± 9, 75 ± 10, and 81 ± 12 mmHg at 0, 30, and 90 minutes after inhalation, respectively; P = 0.410. Heart rate: 71 ± 12, 72 ± 11, and 69 ± 13 bpm at 0, 30, and 90 minutes after inhalation, respectively; P = 0.873).

[0549] As shown in Figure 5, compared with smoking, the current usage pattern of the patients, all patients selected a lung delivery device using an MDI device as a preferred treatment pattern for themselves (satisfaction score was 9.37 ± 0.52 compared with 5.37 ± 2.61, 95% CI of the mean difference: [1.72, 6.28]; P = 0.004).

[0550] As described above, according to the clinical trials involving low-dose THC released from cannabis and delivered by inhalation, the harmful effects observed in the trials were minimal, reversible, and rapidly subsided. There were no participants who withdrew due to tolerance issues.

[0551] Example 2 Comparative analysis The data obtained from the tests described in Example 1 were analyzed in comparison with smoking, oral mucosa, oral and intravenous administration of Δ 9 -THC and inhalation using a commercially available Volcano® vaporizer. Δ 9 -Plasma C per 1 mg of THC administration max Level: The inventors compared the THC yields obtained via pulmonary delivery according to the method described herein with the data published in the art (background art). The comparison results are shown graphically in Figure 6.

[0552] Therefore, Δ 9 -Intravenous administration of THC is the highest Δ9 - Plasma C per 1 mg of THC administered max The levels indicated -43.8 (Non-Patent Literature 9; column labeled "Ohlsson(3)" in Figure 6), and Δ32.8 and 23.8 ng. 9 - THC / plasma ml (reported in Non-Patent Literature 10; column labeled "D'Souza (14)" in Figure 6).

[0553] Δ 9 - Among alternative modes of administration of THC, Δ available in the cannabis substance used 9 - Plasma C per 1 mg of THC max The increase was highest among the lung delivery methods described herein—6.1–9.0 for Volcano® vaporizers (columns labeled “Abrams(9)” and “Abrams(20)”; Non-Patent Literature 11; Non-Patent Literature 12), and an average Δ of 12.3 ng / ml / mg compared to 0.6–4.6 for regular cigarettes (columns labeled “Ohlsson(3)”, “Hunault(15)”, “Hunault(16)”, and “Huestis(17)”: Non-Patent Literature 13; Non-Patent Literature 14; Non-Patent Literature 15). 9 - THC.

[0554] The ratio of THC absorption and distribution due to smoking determines C max This can lead to unnatural results in the sampling protocol; that is, randomly sampling at numerous individual peaks and valleys after each puff can produce unnatural peak responses. This constraint leads researchers to use a rate-adjustable continuous sampling pump to rapidly and sequentially collect blood for the purpose of characterizing the absorption phase of marijuana smoking. From researchers, 1.75% or 3.55%Δ 9 -Δ observed after the first puff of THC tobacco 9 -Average C per 1mg of THC max The increases were reported to be 3.54 or 4.28 ng / ml, respectively. The smoking protocol consisted of a 2-second inhalation, a 10-second holding period, a 72-second exhalation, and a pause.

[0555] The results obtained by the present inventors were 2.9 to 3.5 times higher than those obtained by Huestis et al., which may be indicated by one or more of the following: a 33% longer inhalation time, absence of sidestream smoke, and minimal thermal decomposition of THC during the vaporization process in the MDI device (Figure 6).

[0556] THC's C max Interpersonal variability in: Figure 7 shows the peak plasma Δ obtained by the method described herein. 9 -Data on inter-individual variability in THC concentration and comparative data known in the art (background art) are shown. As shown in Figure 7, the C of the MDI apparatus according to an embodiment of the present disclosure max The inter-individual variability was 25.3%.

[0557] Several studies have reported coefficients of variation (CV) of 47–85% for vaporizers (columns labeled "Abrams(9)" and "Abrams(20)" in Figure 7), 32–115% for tobacco (columns labeled "Ohlsson(3), "Hunault(15)" and "Huestis(17)"), 42–115% for oral administration (Ohlsson(3), Karschner(4), and Lile(21); Non-Patent Literature 16; Non-Patent Literature 17), and 59–67% for transoral mucosal delivery (Karschner(4)), as shown in Figure 7.

[0558] Most of the studies shown in Figure 7 were conducted under controlled drug administration and experimental conditions. Higher inter-individual variability is expected under "real-life" conditions.

[0559] C max The relatively low variability between results may be due to the characteristics of the diagnostic MDI device, which ensures complete and highly efficient delivery of vaporized medication(s) to the lungs, regardless of the individual patient's inhalation pattern.

[0560] Example 3 Treatment window determination and personalization of PD profile In accordance with the personalized lung delivery method described herein, the dose and regimen were calculated using an algorithm specifically developed for the metered-dose inhalation device used according to some embodiments of this disclosure, in order to maintain a 3-hour treatment within a predetermined treatment window for an individual patient referred to herein as "Patient X". The treatment window calculation was based on the THC concentrations in plasma and body known in the art (the THC PK profile) combined with PK change factors of Patient X (e.g., BMI, age, sex, etc.) as described above.

[0561] For patient X, the dosage (multiple predetermined vaporization amounts) and regimen (inter-dosing time) were determined by an algorithm. This algorithm simulates the patient's pharmacokinetic profile based on the above-mentioned PK tests and other PK tests performed on the subject population, as well as population PK change factors, in combination with the PK effects defined above for the MDI device as needed. In parallel, it simulates the predicted pharmacokinetic profile, taking into account the desired therapeutic effect level and the tolerable adverse effect level. Therefore, the resulting predicted PD profile is equivalent to a treatment window that allows for both symptomatic treatment (pain relief) and tolerable levels of psychoactive activity (CNS-related adverse psychoactive effects) in patient X.

[0562] This algorithm provides a desirable medication regimen and treatment plan to achieve a desirable PD profile, based on PK effects and change factors.

[0563] Figure 8 shows a typical example of lung delivery of three predetermined vaporization doses (calculated drug doses) over a 3-hour period for patient X. Patient X is a 35-year-old male with a BMI of 22.

[0564] According to the predicted PK / PD profile, as shown by the red curve in Figure 8, in order to maintain the THC effect within a 3-hour therapeutic window, patient X needed to inhale THC vaporized from cannabis using the quantitative MDI device used in Examples 1 and 2 above, according to some embodiments of the present disclosure, at the following time intervals and predetermined vaporization amounts (calculated dosage and regimen): 00 min - 1.2 mg; 10 min - 1.0 mg; and 60 min - 0.5 mg. The blue curve shows the calculated PD profile at the indicated dosage. As shown in the figure, the calculated regimen maintains patient X within tolerable harmful CNS activity levels, i.e., below the level of adverse effects and above the minimum level of symptom recognition (i.e., above the minimum therapeutic effect).

[0565] The MDI devices and algorithms used in the lung delivery methods described herein enable the use of such MDI devices to deliver an active drug to the lungs at a predetermined vaporization volume (one or more) (predetermined dosage and regimen), thereby obtaining a desired pre-selected PK profile selected to obtain a pre-selected (desired) PD profile, and calibrating and configuring the MDI device based on PK / PD data and individual PK change factors and / or data to obtain the drug effect within a predetermined therapeutic window selected for the individual patient.

[0566] The following is an example of a procedure for determining and administering an individual's dosage and / or regimen for treating a human subject by pulmonary delivery using an inhalation device according to some embodiments of the present disclosure. The procedure is shown in flowchart 1900 in Figure 19.

[0567] The patient data to be provided (see 1901 in Figure 19) may include, for example, information on one or more patient characteristics such as age, sex, weight, BMI, and estimated activity; recommended dosage and / or regimen; and / or the syndrome or indication to be treated. Where necessary, the patient data to be provided (1901) may also include PK / PD data obtained from one or more past inhaler uses for the same active agent(s), and possibly for the same indication. Where necessary, the patient data to be provided (1901) may include correlations or sets of correlations between a patient's dose and PK profile and / or PD profile over a period recorded for one or more past deliveries of the same pharmaceutically active substance. Where necessary, the patient data to be provided (1901) may include data collected from the PK / PD profiles of multiple users or the population to which such users belong.

[0568] Where necessary, patient data (1901) may include treatment instructions and / or treatment preferences. Some examples of treatment instructions or preferences include not administering within a certain time window; increasing hypnotic state overall (e.g., for bedridden patients) or at certain times (e.g., for initial treatment and / or nocturnal and / or when dealing with severe symptoms); and requiring wakefulness within certain time frames. Such instructions may be weighted; for example, a patient may not need to adhere too strictly to some instructions and other subsequent instructions, for instance, a patient may want increased sleepiness at night but be instructed to be awake at 10 a.m. for a test.

[0569] Instructions can sometimes have a relative effect, meaning that certain behaviors are permissible to a certain extent only in order to comply with the given command. For example, an instruction might state that the patient must remain awake while driving unless pain exceeds a certain level.

[0570] If there is anything else included in the voluntary provision of patient data (1901), it is the ability to provide treatment instructions at any point during the treatment period; for example, before the start of treatment, the patient can provide treatment instructions and / or treatment preferences. Thereafter, the patient can enter additional instructions and / or preferences at any time. For example, the patient can use the user interface associated with the device at any time to provide instructions regarding future (e.g., next) doses (or multiple doses). Such instructions may include not administering a certain dose within a given time window, or that it must be administered before a given point in time. If necessary, such instructions may include adjustments to the treatment window that are acceptable and / or preferred for the user, constituting sufficient therapeutic effect and / or maximum level (tolerable) adverse effects.

[0571] If necessary, the provision of patient data (1901) should be updated to reflect the time the dose was inhaled, the amount administered, and / or how the device performed during the inhalation event (e.g., whether the inhalation was successful or failed due to device malfunction and / or improper use). This may be considered an indicator of the user's condition and / or device malfunction and / or the amount of active substance inhaled (efficiency element). Such data may be used to adjust the regimen and / or issue notifications to the user and / or physician.

[0572] If necessary, when the regimen requires the user to administer a certain dose, the user may be prompted to do so visually and / or audibly through at least one user interface. When prompted, the user can postpone the dose by selecting the "snooze" option and, if necessary, set the next time they wish to take the dose. In response, the device may readjust the regimen (e.g., the next dose size and timing) and / or notify the user if this is not possible or may cause a given adverse effect.

[0573] If necessary, if the user forgets the time slot allocated for a given dose, one or more of the following may be done: (a) adjust the regimen to compensate for the delay; (b) notify the user (perhaps by an alarm and / or vibration); (c) notify the caregiver and / or healthcare provider.

[0574] The initial dosage and / or regimen preparation (see 1902 in Figure 19) is performed as follows: Based on the recommended dosage and / or regimen (see details below) and patient data (1901), an initial dosage and / or regimen (1902) is proposed. The initial dosage and / or regimen (1902) may include the recommended dosage according to known standards and / or may be adjusted by considering data on the patient's previous treatment (single or multiple doses) and treatment instructions and / or preferences when using an inhaler.

[0575] Given the recommended dosage and / or regimen, treatment instructions may include several stricter constraints than other instructions. For example, the maximum approved dose should not be exceeded regardless of user preference, and the device may be configured to prevent overdose. Similarly, a minimum essential dose may be prescribed and should not be avoided regardless of user preference, and the device may be configured to issue a non-compliance warning to the user and / or caregivers and / or medical staff in such cases. Where necessary, constraints may be imposed in advance (e.g., based on the therapeutic index of one or more active substances and / or according to a plan designed or approved by the physician), and / or periodically or continuously (e.g., as a result of specific events encountered by the user as a result of using the device).

[0576] If necessary, the preparation of the initial regimen (1902) is performed on the patient when the inhaler and regimen are first assigned. In such cases, the patient should inhale the initial dose or the first few doses under supervision (e.g., for more than two hours). During this period, the patient's symptoms and PD effects are observed, recorded, and measured before the first administration and, if applicable, at least during the su...

Claims

1. A system for delivering at least one active substance to the lungs, wherein the system is An inhalation device for delivering multiple doses of the at least one active substance to individual users at predetermined time intervals, Mobile phones and The mobile phone is equipped with, Means for receiving information on the actual dose administered from the inhalation device, Means for collecting data from individual users regarding at least one effect induced by the at least one active substance, by obtaining feedback data through interaction with the user, including indications of the level of therapeutic effect and / or the level of adverse effect perceived by the user, A storage means for storing the aforementioned feedback data, Means for transferring the collected feedback data to at least one of the following: an external device, the inhalation device, a physician, and the user. Means for generating proposed regimens for multiple doses of the at least one active substance based on the collected feedback data and the information on the actual doses administered, Configured to provide, The generated information on the proposed regimens for the plurality of doses is used by the inhalation device for the subsequent delivery of the at least one active substance in the system.

2. The system according to claim 1, wherein the feedback data includes an indication of the level of therapeutic effect and an indication of the level of adverse effect as perceived by the user.

3. The system according to claim 2, wherein the adverse effects include psychoactive effects, and the mobile phone is configured to automatically estimate the user's psychoactive state.

4. The system according to any one of claims 1 to 3, wherein the mobile phone is configured to obtain the feedback data after the user inhales from the inhalation device.

5. The system according to any one of claims 1 to 4, wherein one or more components of the mobile phone are configured to function as sensors for obtaining the feedback data.

6. The system according to any one of claims 1 to 5, wherein the interaction with the user includes one or more games and / or tasks.

7. The system according to claim 6, wherein the task includes manually and / or visually tracking a target.

8. The system according to any one of claims 1 to 7, wherein the mobile phone is configured to receive instructions and / or requests from the user relating to one or more of the delivery timing, acceptable adverse effects, and desired therapeutic effects.

9. The system according to any one of claims 1 to 8, wherein the mobile phone is configured to generate the proposed regimen of the at least one active substance.

10. The system according to any one of claims 1 to 9, wherein the inhalation device comprises a cartridge containing a plant material in which the at least one active substance is vaporized and delivered to the user.

11. Receiving information on the actual dose administered from an inhalation device for lung delivery of at least one active substance, Receiving user feedback data regarding the amount of therapeutic effect and / or adverse effect experienced by the user of the inhalation device, The aforementioned feedback data is stored, The collected feedback data is to be transferred to at least one of the following: an external device, the inhalation device, a physician, and the user. To generate proposed regimens for multiple doses of the at least one active substance based on the collected feedback data and the information on the actual doses administered. A mobile phone configured to perform the following actions.

12. The mobile phone according to claim 11, wherein the adverse effect includes a psychoactive effect, and the mobile phone is configured to automatically estimate the user's psychoactive state.

13. The mobile phone according to claim 11 or 12, wherein the mobile phone is configured to obtain the feedback data after the user inhales from the inhalation device.

14. The mobile phone according to any one of claims 11 to 13, wherein one or more components of the mobile phone are configured to function as sensors for obtaining the feedback data.

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