Inhalable dry powders

Abstract

To provide inhalable dry powder compositions comprising cannabinoids, useful in the treatment of diseases and disorders, including pain.SOLUTION: A dry powder pharmaceutical composition comprises microcrystalline particles of 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine and a cannabinoid, where the cannabinoid is in an amount from 1% to 40% (w / w) of the total weight of the composition.SELECTED DRAWING: None

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Patent Application No. 62 / 822,303, filed March 22, 2019. No. 6,333,625, filed on Oct. 13, 2003, the disclosure of which is hereby incorporated by reference in its entirety. The specification is incorporated by reference.

[0002] The present disclosure relates to inhalable dry powder formulations containing cannabinoids and methods of use thereof. In particular, the formulations are packaged in replaceable cartridges or cartridges for medicinal deep lung delivery. For use with single or multiple use dry powder inhalers used with capsules is the intention. [Background technology]

[0003] Drug delivery to pulmonary tissue is achieved using metered dose inhalers and dry powder inhalers to treat localized diseases or disorders. This has been achieved using a variety of inhalation devices, including nebulizers and inhalers such as nebulizers. Dry powder inhalers used to deliver medicines include a dispensing mechanism for the powder formulation, and The formulation is usually supplied in bulk or measured into individual doses and packaged in hard gelatin capsules. / Whether contained in unit dose compartments such as cartridges or blister packs The bulk containers contain a single dose of this powder that can be dispensed by the patient immediately prior to inhalation. A metering mechanism is provided to separate the doses.

[0004] To obtain an inhaler with reproducible dosing, the drug formulation must be uniform and the drug must be delivered to the subject. It is necessary that the dose administered is consistent and produces reproducible results. Therefore, ideally, the drug delivery mechanism would be designed to deliver all of the drug while the patient is inhaling to self-medicate. It is necessary to operate in such a way that the drug is effectively and completely discharged. It is not required that the powder be completely expelled from the inhaler, provided that the drug can be delivered. Regarding this point, when using powder formulations in bulk containers, when using separate unit dose compartments, In comparison with blister packs, flowability and long-term physical and mechanical stability are of greater importance. For unit dose compartments such as Due to the materials used to manufacture the Lister, air may be trapped in the drug compartment. It is possible that subsequent storage of the formulation for extended periods may result in hygroscopic properties, particularly if the formulation to be delivered is hygroscopic. If this occurs, viability is lost. In addition to this, the drug delivery system is also known to be a barrier to inhalation. Dry powder inhalers use blisters to inject the liquid into the blister film, which is punctured. The shape of the air duct structure may vary due to the film being peeled off, which may cause airborne particles to enter the lungs. A drawback can be that the delivered dose is not consistent.

[0005] Dry powder inhalers are either breath activated or breath powered. The drug particles in the carrier can be entrained in an air stream. The drug can be delivered to the patient by inhalation using a fine, dry powder that Therefore, efficient drug delivery to the lungs and systemic circulation requires that the formulation be delivered as aerosolized particles. It also depends in part on the quality of the product produced, the type of drug being delivered, and the delivery mechanism used. The advantages of delivering topical drugs to the lungs include the large surface area and the ease of absorption by the mucosal surfaces of the lungs. The main reasons for this include the fact that

[0006] There are many drawbacks to using pulmonary drug delivery mechanisms. For example, some devices use propellants. This can have adverse effects on the user and on the compound being delivered, and can also affect the active Agents (including but not limited to small molecules and biological agents such as proteins and peptides) When aerosolized, the activity of the drug may be altered. There is a possibility of excessive drug / formulation loss during aerosolization. Another problem with all drug delivery is the ability to pass drugs through natural barriers, such as the cilia that line the trachea. problems in trying to get all of the drug through the tube and in trying to administer the drug in a uniform volume and weight. The problem is that it is difficult to deliver drugs to the lungs due to problems in administering drugs. In the pulmonary delivery of substances, in particular in the development of suitable inhalable formulations and effective delivery mechanisms. There is room for improvement.

[0007] More recently, cannabinoids have been shown to have many beneficial health effects and medicinal uses. For example, the Food and Drug Administration (FDA) recently announced that Dravet syndrome (severe myoclonic epilepsy in infancy) and Lennox-Gastaut syndrome (LGS, There are already several epilepsy medications available for the treatment of seizures caused by severe epilepsy that begins in early childhood. Epidiolex®, an oral cannabinoid liquid for patients who have failed The company approved Marinol (Dro), an oily resin contained in capsules. Navinol is an inhibitor of nausea and vomiting caused by chemotherapy drugs used in cancer treatment. It is used as an emetic and to stimulate the appetite in anorexic AIDS patients. Cesamet (nabilone) is also a synthetic drug that comes in an oral capsule. It is a cannabinoid that is used to treat nausea and vomiting caused by chemotherapy drugs used in cancer treatment. It is used to suppress vomiting. Cardiac and emetic control may not effectively treat these conditions. Summary of the Invention [Problem to be solved by the invention]

[0008] Thus, for treating these and many other conditions, and for use in treating these types of medications, To achieve consistent and reproducible delivery of cannabinoids to facilitate the administration of There is a need to develop new formulations or compositions and new routes of administration for this purpose. Therefore, the inventors have developed a distinct and efficient dry powder inhaler to deliver cannabinoids. The need to design and manufacture inhalable cannabinoid compositions that deliver a consistent and effective dose of confirmed. [Means for solving the problem]

[0009] overview The present disclosure relates to diseases, disorders, and conditions, including cancer, epilepsy, and eating disorders, and to treatment of diseases. A therapeutically effective amount of a cannabis-derived molecule or cannabis extract for treating symptoms such as nausea and vomiting associated with The present invention relates to a dry powder composition for pulmonary delivery comprising a vinoid. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] In certain embodiments, the compositions include synthetic cannabinoids, naturally occurring cannabinoids, and / or extracted cannabinoids and one or more pharmaceutical agents suitable for pulmonary delivery. In some embodiments, the composition may further comprise a physiologically acceptable carrier and / or a pharma- ceutically acceptable excipient. In this embodiment, the cannabinoid molecule may be a naturally occurring extracted cannabinoid or a synthetic Cannabinoids may include, but are not limited to, tetrahydrocannabinol, cannabinol (THC), cannabidiol (CBD), and cannabinol, Included are derivatives of these, as well as combinations thereof.

[0011] In certain embodiments, the pharma- ceutical acceptable carrier includes fumaryl diketopiperazine. Diketopiperazines such as choline; 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and 1,2-distearoyl-sn-glycero-3-phosphocholine (DSP C) lipophilic compounds such as phospholipids; mannitol, lactose, and xylitol buffers such as phosphates, citrates, and tartrates, and the like; In one embodiment, the content of phospholipids added to the composition is In one embodiment, the amount of phospholipid added depends on the type of phospholipid added. It may represent up to 40% (w / w) of the composition.

[0012] In one embodiment, 3,6-bis(N-fumaryl-4-aminobutyl)diketopipera A dry powder pharmaceutical composition comprising microcrystalline particles of a diketopiperazine, such as diketopiperazine, The composition has a mean pore size of about 23 nm to about 26.2 nm. In one embodiment, the dry powder pharmaceutical composition has a surface area of ​​about 59 m 2 / g ~ approx. 63 m 2 / g range of fine crystal particles.

[0013] In some embodiments, the dry powder pharmaceutical composition comprises microcrystalline particles, The pore characteristics are as follows: average pore volume is about 0.43 cm 3 / g, and the average pore size is 23 nm to about 2 It is 8nm.

[0014] In other related embodiments, the dry powder composition for delivery to the airways and lungs is For example, cannabinoids and self-assembled crystalline forms, amorphous powder composition forms, and / or Most of the diketopiperazines are in the form of microcrystalline powders that do not self-assemble in suspension. or combinations thereof and / or crystalline complex dry powders; and a cannabinoid active agent. In the dry powder, the diketopiperazine is not added to any other carrier and / or excipient other than the diketopiperazine. Combinations with topiperazine, e.g., monito, xylitol, trehalose The composition may further comprise a sugar, such as sucrose, and a cannabinoid active agent.

[0015] In certain embodiments, the dry powder composition is provided in a single-use personal inhaler. The cannabinoid compositions may also be provided in replaceable form for use with multi-use inhalers. The composition may also be provided in a single-use cartridge or capsule. The cell contains a dry powder for inhalation. The dry powder is delivered to the pulmonary circulation via a local and / or systemic route. It can be put to good use.

[0016] In one embodiment, the dry powder inhaler is a small, reusable or disposable, breath-actuated The inhaler can be a powdered inhaler, available in a variety of shapes and sizes, and can effectively deliver powdered medicine to the lungs and systemic circulation. In some embodiments, the dry powder is The inhaler includes a container for holding a single-use powdered medicament. In this case, the multi-use inhaler may include replaceable containers and / or cartridges. In these embodiments, the dry powder inhaler can provide a reduced airflow resistance during inhalation in use. It is configured to generate values ​​of approximately 0.05 to approximately 0.25 (√kPa) per liter per minute. In this and other embodiments, the dry powder inhaler effectively delivers a dose of dry powder. To deliver the drug, a pressure difference of at least 2 kPa, preferably 2 kPa to about 8 kPa, is generated. It can be done.

[0017] In another embodiment, a breath actuated dry powder inhaler and a and a cartridge or capsule containing a dry powder, such as a dry powder cannabinoid medicine. An inhalation mechanism is provided, and the medicament is administered, for example, by crystals self-assembling in suspension to form particles. The present invention relates to a crystalline form, an amorphous form, and / or a crystalline complex powder in which the crystals do not self-assemble in suspension. and a diketopiperazine in microcrystalline form, including but not limited to, a powder, or a combination thereof; In an alternative embodiment, the composition may include a drug formulation for pulmonary delivery, such as a composition comprising: The dry powder may optionally further contain other carriers and / or excipients other than the diketopiperazine, e.g. For example, sugars such as mannitol, lactose, trehalose, sorbitol, and xylitol. and an active agent. In some embodiments, for use in an inhalation mechanism The dry powder composition has the formula 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diaminopropyl. Contains diketopiperazines which are ketopiperazines.

[0018] In certain embodiments, the composition is extracted from a natural source or synthetically produced. The composition may contain cannabinoids, and may comprise from about 0.1% (w / w) to about 50% or less of the total weight of the composition. In some embodiments, the composition comprises cannabinoids. The amount of the compound is about 0.1% to about 10%, about 0.5% to about 20%, about 0.5% to about 5% by weight of the total weight of the composition. It may contain 0%, or about 1% to about 75%.

[0019] In one embodiment, precipitating diketopiperazine crystalline particles in an aqueous suspension; washing the crystalline particles in the precipitate, for example using tangential flow filtration; adding the cannabinoids in an ethanol solution; and optionally filtering or winterizing the solution. The fatty acid layer was removed; and the phospholipids were treated with diketopiperazine. adding the compound to a suspension containing the opiperazing particles; and spray drying the suspension. producing a bulk cannabinoid powder by; A method of manufacturing something.

[0020] In certain embodiments, the inhalation mechanism involves, for example, local or systemic delivery of a medication. Methods for treating conditions, e.g., diseases and disorders, e.g., cancer, glaucoma, HIV / A IDS, muscle spasms, severe pain, severe nausea, cachexia or significant weight loss, muscle atrophy, and other disorders In some embodiments, the method can be used in a method for treating a condition. The present invention relates to a method for administering to a subject in need of treatment a composition comprising a diketopiperazine and a cannabinoid. and administering to the patient at least one dose via the inhaler at least one to one or more doses of the active ingredient. The inhaler uses the subject's own breath to deliver the inhalation and allows the subject to inhale for six seconds. The composition may comprise a container, cartridge, or capsule in a dosage arrangement for use.

[0021] In one embodiment, the dose comprising the cannabinoid and the diketopiperazine is administered by high resistance inhalation. The container can contain about 1 mg to about 20 mg of powder or about 1 mg to about 10 mg of powder. In one embodiment, the cannabinoid composition has a powder content for pulmonary delivery of at least 0. Contains 1 mg or at least 0.5 mg.

[0022] In some embodiments, there is provided a dry powder drug delivery system comprising a dry powder inhaler comprising a dry powder pharmaceutical composition comprising microcrystalline particles of 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine and a cannabinoid, wherein the amount of cannabinoid is 1%-40% (w / w) of the total weight of the composition, and the microcrystalline particles have an average pore volume of about 0.43 cm as measured by BJH adsorption. 3 / g, and the average pore size is in the range of about 23.8 nm to 26.2 nm.

[0023] In one embodiment, the dry powder inhalation system is a composition for treating a particular disease or disorder. The kit includes at least one component of an inhalation mechanism, such as an inhaler containing the substance.

[0024] In one embodiment, a method is provided for treating pain, including chronic pain, in a patient, comprising: The method includes administering to the patient a dry powder inhaler and a cannabinoid-containing and administering to the patient an inhalation mechanism comprising a pharmaceutical dry powder composition comprising: administering the dry powder composition to the patient by deep inhalation from an inhaler; Includes.

[0025] In an alternative embodiment, the inhalation mechanism comprises a dry powder inhaler and a dry powder pharmaceutical composition. the dry powder pharmaceutical composition comprises a cannabinoid, an antiviral The therapeutic agent may include one or more of an anti-inflammatory, anti-biotic, or anti-inflammatory compound, or a combination thereof. In one embodiment, the antiviral compound is used to treat respiratory infections or In one embodiment, the antiviral compound is an acetonitrile. The active ingredient is selected from salicylates such as salicylic acid, curcumin, and / or vitamin C. In one embodiment, the dry powder pharmaceutical composition contains lactose, mannitol, trehalose. , xylitol, and other sugars; 3,6-bis(N-fumaryl-4-aminobutyl)-2,5- Diketopiperazines and their derivatives such as diketopiperazine; citrates; tartrates; or other pharma- ceutical acceptable excipients and / or carriers for pulmonary delivery. In one embodiment, the dry powder composition may comprise 3,6-biphenyl or a salt thereof. (N-fumaryl-4-aminobutyl)-2,5-diketopiperazine or its salts and Cumin may be included in an amount up to 50 mg of powder by weight per dose.

[0026] In other embodiments, the dry powder composition comprises a diketopiperazine or its disodium salt. and curcumin alone, and optionally acetylsalicylic acid, in an amount ranging from 0.5% to about 20% by weight of the composition. % by weight or about 1 wt% to about 10 wt%.

[0027] For treating viral diseases, particularly respiratory track infections and pulmonary infections The method comprises administering to a subject in need of treatment a dry powder pharmaceutical composition comprising curcumin or a derivative thereof. In the composition, 0.5wt% to about 20wt% and 3,6-bis(N-fumary) Particles of (4-aminobutyl)-2,5-diketopiperazine and, optionally, one or more pharmaceutical agents. and a pharmaceutical excipient or carrier, and administering a therapeutic dose of a dry powder pharmaceutical composition comprising the composition. In another embodiment, the dry powder composition contains a salicylate, such as acetylsalicylic acid. It may further include:

[0028] Detailed Description In embodiments disclosed herein, a dry powder containing a medicament is orally inhaled by a subject. The present invention describes a dry powder composition for use with a dry powder inhaler for delivery by inhalation. In one embodiment, the composition is administered as a dry powder inhaler that is respiratory-actuated by an individual's inhalation. It is intended for use with an inhaler, either for single use as a disposable inhaler or for multiple In an exemplary embodiment, the method includes the steps of: The inhaler may be designed for single use, and the cannabinoid formulation may be contained within the inhaler. The inhaler is provided with a 250mg capsule, and the inhaler is manually actuated to a dosing configuration, thereby dispensing the 250mg capsule to be inhaled. In an exemplary embodiment of the multi-use inhaler, the cannabinoid formulation is accessible. The inhaler is provided empty and a capsule or cartridge containing the cannabinoid composition is inhaled. The container is placed / attached to the inhaler, and upon insertion, the container automatically or subsequently The mechanism that is used to place the device in the inhalation position is determined by the inhalation mechanism. For example, the carrier mechanism may be Closing the inhaler creates an air passage within the cartridge, which allows air to reach the inhaler through the air conduit. In one embodiment, the capsule or cartridge may be The device does not contain inhalable cannabinoid dry powders, such as pharmaceutical formulations, but does contain inhalable cannabinoid dry powders, such as pharmaceutical formulations.

[0029] The dry powder inhaler comes in various shape and size embodiments and is reusable; Easy to use, inexpensive to manufacture, and / or made of plastic or other acceptable materials The dry powder inhaler can be manufactured in large quantities in a simple process using the method described herein. Various embodiments of the inhaler are provided, and generally, the inhalation mechanism comprises an inhaler and a powder-filled cartridge. It also includes a cartridge.

[0030] As used herein, the term "disposable inhaler" refers to an inhaler that is intended for single use. The inhaler is provided with a dose of powder. The inhaler is adapted to dispense its powder contents after a single use or It is inhaled and then discarded.

[0031] As used herein, the term "unit dose inhaler" refers to a single inhaler that contains a dry powder formulation. and adapted to receive a single cartridge or container, and dispense a single dose from the single container. Refers to an inhaler that delivers a dry powder formulation to the user via inhalation. Recognize that multiple unit doses may be required to provide the prescribed dose to the user. It should be understood that in one embodiment, the unit dose inhaler is capable of multiple uses. It is.

[0032] As used herein, a "cartridge" refers to a cartridge configured to hold or contain a dry powder formulation. The enclosure for containing the powder includes a cup or container and a lid. The cartridge is made of a high rigidity material, and the cup or container is subjected to a translational movement relative to the lid. more mobile, or vice versa.

[0033] As used herein, "powder agglomeration" refers to the formation of agglomerates of powder particles or It refers to an agglomerate with irregular geometric dimensions such as width, diameter, and length.

[0034] As used herein, a "unit dose" refers to a pre-metered dry powder formulation for inhalation. Alternatively, a unit dose refers to a single metered amount that can be delivered via inhalation. It may be a single container containing several doses of the formulation. A unit dose cartridge / container is: Alternatively, it may be a plurality of individually deliverables each containing a unit dose. The subdivision may include a subdivision of

[0035] As used herein, the term "about" refers to a value to which the value is to be measured. It is used to indicate that the standard deviation of error of the equipment or method employed is included.

[0036] As used herein, the term "particulate" refers to a particle without regard to its precise external or internal structure. It refers to particles with a diameter of about 0.5 to about 1000 μm. Fine particles in the bloodstream can reach the lungs and successfully pass through most of the natural barriers. If the diameter is less than about 10 microns, it is necessary to induce a bend in the larynx. However, if the diameter is about 0.5 μm or more, it is necessary to prevent it from being expelled. In order to reach the deep lung (or alveolar region) where absorption is thought to be most effective, It is preferable to maximize the proportion of particles contained in the "respirable fraction" (RF), Fractions (RF) can be prepared using standard techniques, e.g., Anderson Cascade Particles with an aerodynamic diameter of about 0.5 to about 6 μm as measured using an impactor. It is generally accepted that the range is 100% (although some references use slightly different ranges). ). The aerodynamic particle size is measured using the NEXT GENERATION IMPACTOR ( Also used with other impactors such as NGI (TM), MSP Corporation In this case, the inhalable fraction may be of a similar aerodynamic diameter, e.g., <6.4 μm. In some embodiments, particle size is measured using a laser diffraction instrument, e.g. , U.S. Pat. No. 8,508,732 (the entire relevant teachings relating to laser diffraction therein); The laser diffraction apparatus disclosed in the above publication, which is incorporated herein by reference, is used. In order to evaluate the performance of the inhalation mechanism, the geometric volume median diameter (VMD) of the particle is used. c) Median geometric diameter (VMGD) is measured. For example, in various embodiments, ≧80%, 85%, or 90% of the cartridges When empty, the VMGD of the emitted particles is <12.5μm, <7.0μm, or <4.8μm. m indicates that the aerodynamic performance is better in this order.

[0037] Respirable fraction on fill (RF / fill) refers to the discharge of the filled powder contents for use as a dose. The percentage (%) of powder in the dose that is suitable for inhalation and is discharged from the inhaler in The percentage of particles emitted that are suitable for pulmonary delivery from the delivered dose is It represents the aerodynamic performance of a particle, which is a measure of the aerodynamic performance of the particle. If the fill value is 40% or more, the characteristics in terms of aerodynamic performance will be unacceptable. In certain embodiments disclosed herein, the ratio of inhalation to filling volume is In an exemplary embodiment, the absorbency to loading amount is greater than 50%. The insoluble fraction can be up to about 80%, where about 80% of the loading is standard Using the technique, particle sizes measured are <5.8 μm.

[0038] As used herein, the term "dry powder" refers to a powder that is suspended in a propellant or other liquid. This refers to a fine particulate composition that is not dissolved or dissolved. This does not necessarily mean that the water molecules are completely present. This is not meant to suggest that there is no

[0039] As used herein, "amorphous powder" refers to powders that have no distinct repeating forms, shapes, or structures. It refers to a dry powder that is free of visible crystallinity and includes powders that are completely amorphous.

[0040] In a related exemplary embodiment, the device may be used in several ways and in various ways. In one embodiment, the inhaler and cartridge can be manufactured from a variety of materials, e.g. For example, injection molding techniques, thermoforming, blow molding, pressing, 3D printing, and the like can be used to create plastic. Polypropylene, cyclic olefin copolymers, nylon, and other compatible polymers, as well as The casing may be made using various types of plastic materials such as acrylic, acrylic resin, and the like. In the dry powder inhaler, the individual components are assembled in a top-down manner. In some embodiments, the device can be assembled using a self-assembled assembly. Thus, inhalers are generally available in small sizes, e.g., having dimensions ranging from about 1 inch to about 5 inches. Generally, the width and height are less than the length of the device. They come in a variety of shapes including rectangular bodies, cylindrical, elliptical, cylindrical, square, and oblong. Other shapes such as rectangular, circular, etc. may also be used.

[0041] In the embodiments described and illustrated in this regard, the inhaler includes a flow of air into the inhaler. The dry powder formulation can be efficiently sterilized by using at least one relatively rigid flow conduit that allows For example, inhalers contain a device that effectively fluidizes, deagglomerates, or aerosolizes the dry powder. a first air flow passage leading into and extending from a cartridge housing the cartridge; A second air flow path is provided that can merge with the first air flow path extending from the The flow conduit may have a variety of shapes and sizes depending, for example, on the configuration of the inhaler. In one embodiment, the inhaler has a kinetic energy of, for example, about 0.055 to about 0.250 (√kP a) It is a high resistance inhaler with a resistance value of 1 / liter per minute. Therefore, in this mechanism Therefore, if the peak pressure drop during inhalation is between 2 and 20 kPa, the result is a peak The flow rate is between about 7 and 70 liters per minute. This allows for a filling volume of 1 to 50 m g, greater than 75% of the cartridge contents are expelled. These performance characteristics are achieved by a single inhalation by the end user and are delivered by the cartridge. The rate of powder discharge is greater than 90% of the powder contained in the cartridge.

[0042] In embodiments disclosed herein, the dry powder formulation may be a crystalline powder, an amorphous powder, or The powder can be a combination of these, and the powder can be a consistent powder in less than about 2 seconds from the inhaler. The inhaler mechanism has a high resistance value, about 0.065 to about 0.200 (√kP a) / liter per minute. Therefore, in a mechanism with a cartridge, If the peak pressure drop is between 2 and 20 kPa, the resulting peak pressure in the entire mechanism is The flow rate of the powder is about 7 to 70 liters per minute. More than 75% of the cartridge contents are dispensed, ranging between 0 mg and up to 50 mg. In embodiments, such performance characteristics are achieved by a single inhalation by an end user; The cartridge discharge rate is greater than 90% of the powder contained in the cartridge. In an embodiment, the inhaler and cartridge mechanism is adapted to deliver the powder from the inhaler to the patient. The single-stage process can be performed by discharging the end of the sample as a continuous stream or in one or more pulses. In one embodiment, the dosage arrangement is configured to provide a single dose. The airflow resistance is in the range of 0.065 to 0.200 (√kPa) / liter per minute. and a dry powder inhaler configured to deliver a dry powder formulation to the lungs of a patient, the dry powder inhaler including a conduit. In this and other embodiments, a suction mechanism is provided for causing the suction The overall airflow resistance is relatively constant over the pressure differential range of 0.5 kPa to 7 kPa. .

[0043] The structural configuration of the inhaler produces a respirable fraction of more than 50% and particles smaller than 5.8 μm. The inhaler is a device for dissolving a powdered medicine contained in a container. More than 85% of the air can be expelled during the inhalation maneuver. The inhaler shown in the figure has a pressure of 2 to 5 kPa for a maximum filling range of 30 mg or 50 mg. Discharges more than 90% of the cartridge or container contents in less than 3 seconds with a pressure difference between It is possible.

[0044] Although the inhaler is primarily described as breath-actuated, in some embodiments, the inhaler The injector is a generator for generating the pressure differential necessary to deagglomerate and deliver the dry powder formulation. For example, a nitrogen inhaler can be provided at the air inlet port. It can be adapted to a pneumatically driven source such as a power source that stores compressed gas, e.g., a canister. A spacer may be provided to capture the jet so that the patient can inhale at a comfortable pace. do.

[0045] In the embodiments described in this connection, the inhaler is adapted to deliver a single unit dose. A reusable inhaler may be provided as a reusable inhaler for delivering It can be used multiple times, with the usage limit set in advance depending on the formulation. This means that it will be discarded when it reaches

[0046] Devices and mechanisms useful for pulmonary delivery of the present powders exhibit broad characteristics. and an integral or attachable unit dose cartridge containing the desired powder dose. Pulmonary powder delivery facilitates efficient delivery of the active cannabinoid to the lungs. Carriers and excipients include. Exemplary embodiments include 3,6-bis(N-fumaryl-4-amino Butyl)-2,5-diketopiperazine; Fumaryl diketopiperazine, also known as FDKP It's gin.

[0047] Dry powders produced using diketopiperazines are available in a variety of forms produced by a variety of techniques. By freeze-drying or spray-drying a solution or suspension of the desired cannabinoid formulation In one embodiment, a specific surface area (SSA) of about 15 m 2 / g~approx. 67m 2 / g, the diketopiperazine-based crystalline microparticles have improved aerodynamic properties. They exhibit advantageous properties for delivering drugs to the lung, such as improved optical properties and drug adsorption. In one embodiment, a crystalline FDKP having a high capacity is used in a formulation containing a specific molecule. For example, the specific surface area of ​​the fine particles is 35 m 2 / g, and the specific surface area of ​​such particles is Depending on the amount of active agent, approximately 19 m 2 / g ~ approx. 30m 2 / g range or about 28m 2 / g~approx. 71m 2 / g range or about 19m 2 / g ~ approx. 57m 2 / g range.

[0048] In one embodiment, the dry powder medicament may, for example, comprise a diketopiperazine and an active pharmaceutical ingredient. In this embodiment, the medicament active ingredient or active agent is a The device may be of any type depending on the disease or condition. Topiperazine can be used, for example, as a carrier system for delivering active agents to target sites in the body. Symmetric and asymmetric molecules useful for forming particles, microparticles, and the like that can be The term "active agent" as used herein includes any of the following: Molecules that are referred to as therapeutic agents or include small molecules such as neurotransmitters, such as cannabinoids. When the formulation is formed, the diketopiperazine particles are encapsulated, associated, conjugated, or complexed with the diketopiperazine particles. It can be embodied or encapsulated or adsorbed onto any The cannabinoid form can be combined with a diketopiperazine. The drug delivery mechanism is The purpose of the present invention is to deliver a therapeutic, prophylactic, or diagnostic agent to a patient. It is possible.

[0049] Fumaryl diketopiperazine 3,6-bis(N-fumaryl-4-aminobutyl)-2,5 -Diketopiperazines; FDKP is one of the preferred diketopiperazines for pulmonary applications. Is: [ka]

[0050] Pulmonary delivery microparticles with diameters between about 0.5 and about 10 μm can reach the lungs. , can reach the systemic circulation and deliver the active agent. It is necessary to induce the tube to bend at the larynx. If the tube has a diameter of more than about 0.5 μm, it may be difficult to vomit. Generally, particles with a diameter of more than 10 μm or less than 20 μm are Fine particles above m are useful for localized delivery to the airways and lungs.

[0051] Particles less than 10 microns in diameter successfully pass through most of the natural barriers in the airways and enter the lungs. The embodiments disclosed herein can reach a specific surface area (SSA) of about 15 m 2 / g ~ approx. 75m 2 / g or about 30m 2 / g ~ approx. 71m 2 / g These devices have advantageous properties for delivering drugs to the lungs, such as improved aerodynamic performance and improved drug adsorption. In some embodiments related thereto, a particular trans isomer is A crystalline fiber having a content of about 35 to about 65%, or 45 to about 63%, or 45 to about 60%. A composition is provided that includes malyl diketopiperazine (FDKP) microparticles.

[0052] In an exemplary embodiment, a dicaprylic acid composition for pulmonary delivery containing a cannabinoid active agent is provided. A topiperazine-based composition is provided, the diketopiperazine being fumaryl diketopiperazine. a plurality of substantially uniformly formed microcrystalline particles, the particles being substantially hollow; The microcrystals of diketopiperazine have a spherical structure and do not self-assemble even when a suspension is formed. the particles have a geometric volume median diameter of 5 μm or less; Topiperazine was combined with a solution of acetic acid in the absence of surfactant and incubated in parallel for up to 2, The process involves homogenizing the mixture in a high shear mixer at high pressure (1,000 psi) to form a precipitate. washing the precipitate in the suspension with deionized water; and concentrating the suspension. and drying the suspension in a spray dryer. In some embodiments, the composition comprising fumaryl diketopiperazine and a cannabinoid is Prior to spray drying the suspension, the particles further comprise a phospholipid.

[0053] In some embodiments, a diketopiperazine-based pulmonary delivery system comprising an active agent is provided. The diketopiperazine is a sodium fumaryl diketopiperazine. The composition includes an amorphous powder.

[0054] a) a dry powder containing a cannabinoid medicine; b) a cartridge containing the powder; and a housing. and a mouthpiece; and an inhaler for delivering an inhalable dry powder. Also provided is a mechanism, the cartridge having a gas inlet and a gas outlet, the housing having a cartridge The device is for mounting a screw, and defines two flow paths, a first flow path and a second flow path, One flow path directs gas into a gas inlet of the cartridge, and a second flow path directs gas into a gas inlet of the enclosure. Bypassing the inlet and creating a pressure drop of ≥ 2 kPa across the inhaler, the particle jet enters the mouth. The particles are released from the piece, 50% of the released particles have a VMAD of ≦10 μm, The flow bypassing the gas inlet of the trough is arranged so as to collide with the flow coming out of the enclosure. The nozzle is oriented in a direction substantially perpendicular to the flow direction of the exhaust gas.

[0055] The present disclosure also provides compositions comprising crystalline particle compositions, improved microcrystalline particles, or amorphous powders. Dry powder compositions containing the compounds and methods for making the particles and methods for treating diseases and disorders in a subject and methods for enabling improved drug delivery to the lungs. The embodiments have a high drug adsorption capacity, thereby allowing the drug-containing composition to absorb one or more active agents. Crystalline diketopiperazine, including microcrystalline diketopiperazine particles that produce a powder with high yields Improved delivery is achieved by providing compositions manufactured using the microcrystalline particles. The resulting powder can deliver increased drug loading in a smaller powder dosage, This can facilitate drug delivery to the patient. Depending on the starting material, the powder can have an interface by a variety of methods, including those utilizing surfactant-free or surfactant-containing solutions. It can be manufactured as follows.

[0056] An alternative embodiment disclosed herein is an inhalable liquid comprising a plurality of substantially uniform microcrystalline particles. The dry powder may include microcrystalline particles having a substantially hollow spherical structure. Microscopically, diketopiperazines that do not self-assemble in suspension or solution can be formed and can be porous. In one embodiment, the microcrystalline particles comprise a shell containing the drug crystals. and / or diketones, depending on the drug content and other factors in the process of making the powder. The particles may be substantially hollow spherical and substantially solid particles containing microcrystals of piperazine. In one embodiment, the microcrystalline particles have an average pore volume as measured by BJH adsorption of is about 0.43 cm 3 / g, approximately 0.4 cm 3 / g ~ approx. 0.45cm 3 / g range The average pore size is in the range of about 23 nm to about 30 nm or in the range of about 23.8 nm to 26.2 nm. The particles are relatively porous and are surrounded by a porous layer.

[0057] Certain embodiments disclosed herein provide a powder comprising a plurality of substantially uniform microcrystalline particles. the particles having a substantially spherical structure with a shell which may be porous, The present invention relates to a method for preparing a diketopiperazine nanoparticle having a geometric structure comprising: The median diameter is less than 5 μm; or less than 2.5 μm.

[0058] In certain embodiments herein, up to about 92% of the geometric volume of the microcrystalline particles The median diameter is 5.8 μm. In one embodiment, the shell of the particles is made of entangled diketopy. It is composed of perazine microcrystals with one or more drugs adsorbed on its surface. In some embodiments, the particles are capable of encapsulating a drug within their internal void volume. and / or the drug is adsorbed on the microcrystal surface and entrapped within the internal void volume of the spheres. It may be a combination of drugs.

[0059] In one embodiment, the diketopiper comprises a plurality of substantially uniformly formed microcrystalline particles. A lazin composition is provided, the particles of which have a substantially hollow spherical structure and do not self-assemble. The particles have a shell containing microcrystals of diketopiperazine; the particles have a trans isomer content of Solutions of diketopiperazine ranging from about 45% to 65% were diluted with acetic acid in the absence of surfactants. The solution is then mixed with the cellulose solution and homogenized in a high shear mixer at high pressures up to 2,000 psi. washing the precipitate in suspension with deionized water. concentrating the suspension and drying the suspension in a spray dryer. The method is formed by:

[0060] This method involves spraying an active agent or ingredient, such as a drug or bioactive agent, into the solution prior to the spray drying step. A solution containing the active agent or active ingredient is adsorbed and / or encapsulated on or within the particles. The process may further include adding, with mixing, The particles produced may have a size in the submicron range prior to spray drying.

[0061] In certain embodiments, a diketopycin derivative comprising a plurality of substantially uniformly formed microcrystalline particles is provided. A perazine composition is provided, the particles of which have a substantially hollow spherical structure and do not self-assemble. The particles have a geometric volume median diameter of 5 μm or less and a shell containing microcrystals of diketopiperazine. and the particles were prepared by mixing a solution of diketopiperazine with a solution of acetic acid in the absence of surfactant. The mixture is then combined and simultaneously homogenized in a high shear mixer under high pressure up to 2,000 psi. forming a precipitate by washing the precipitate in the suspension with deionized water. concentrating the suspension and drying the suspension in a spray dryer. is formed.

[0062] This method involves the spray drying of cannabinoid active ingredients dissolved in an alcohol solution prior to the spray drying step. A solution containing a drug and a diketopiperazine are mixed together, and the active drug or active ingredient is placed on or inside the particle. The method further includes the step of adding, with mixing, the soluble polymer so that the soluble polymer is adsorbed and / or encapsulated in the soluble polymer. The particles produced by the process can have a size in the submicron range before spray drying.

[0063] In some embodiments, the diketopy includes a plurality of substantially uniformly formed microcrystalline particles. Perazine compositions are provided, the microcrystalline particles having a substantially hollow spherical structure and not self-assembled. The shell comprises microcrystals of small diketopiperazine and has a median volume geometric diameter of 5 μm or less. The particles are prepared by dissolving a solution of diketopiperazine in the absence of surfactant and in the absence of active agent. The mixture is then mixed with a solution of fresh acetic acid and mixed in parallel in a high shear mixer under high pressures of up to 2,000 psi. forming a precipitate by homogenizing the suspension with deionized water; washing; concentrating the suspension and drying the suspension in a spray dryer; The method comprises the steps of:

[0064] The starting material containing the active ingredient has the appearance of a thick extract or a honey-like viscous consistency. In certain embodiments, the material, the microcrystalline particles, are formed as shown above, Before combining with the extract or gum, these were filtered using tangential flow filtration with water. After washing with water, the resulting particle suspension is freeze-dried to remove the water. After resuspension in an alcoholic solution containing ethanol or methanol, it is available as a solid or In one embodiment, the composition optionally includes an active ingredient in suspension or solution. The method of making the composition comprises adding the active ingredient in parallel with the active ingredient or subsequent to the addition of the active ingredient and prior to spray drying. and one or more amino acids such as leucine, isoleucine, norleucine, and methionine. glycerol, or one or more phospholipids, such as 1,2-dipalmitoyl-sn-glycerol, Celo-3-phosphocholine (DPPC) or 1,2-distearoyl-sn-glycero and optionally adding additional excipients such as dihydrocholine-3-phosphocholine (DSPC). In some embodiments, forming the composition comprises adding an extract containing the desired cannabinoid active agent to Optionally, by filtering or winterizing to increase its solubility, a layer of unwanted material such as lipids may be removed. The method includes the steps of separating and removing the

[0065] The method includes the steps of adding, with mixing, a first solution comprising a diketopiperazine; adding a second solution containing PPC or DSPC; mixing the solutions; and prior to the spray drying step, cannabinoids such as cannabidiol and THC may be added. A third solution containing a vinoid active agent is added to the particles so that the active agent is adsorbed and / or encapsulated on or within the particles. and mixing the solution so that it is incorporated; This process can be carried out with or without homogenization by a high shear mixer. The particles produced by the process can be in the submicron crystal size range prior to spray drying. Alternatively, particles may be formed from a solution during spray drying. Spray dried powders are substantially uniformly dispersed. The particles are of high quality, low density and require very little energy to deagglomerate.

[0066] In some embodiments related thereto, the drug content can be delivered on a freeze-dried or spray-dried crystalline powder using FDKP with a content of up to about 10%, or up to about 20%, or up to about 30%, or more. In embodiments using microcrystalline particles formed from FDKP or FDKP disodium salt, where the particles are not self-assembled and include submicron-sized particles, the drug content can typically be greater than 0.01% (w / w). In one embodiment, the drug content to be delivered with the microcrystalline particles is about 0.01% (w / w) to about 75% (w / w); about 1% to about 50% (w / w), about 10% (w / w) to about 25% (w / w), or about 10% to about 20% (w / w), or 5% to about 30%, or more than 25%, depending on the drug to be delivered. In exemplary embodiments where the drug is cannabidiol or THC, the microparticles typically comprise about 5% to 45% (w / w) or about 10% to about 20% (w / w) or more of the total content of the composition. In certain embodiments, the drug content of the particles may vary depending on the form and size of the drug to be delivered. In some embodiments, the density of the bulk powder, or the density of the bulk containing FDKP in microcrystalline or crystalline complex form, may be less than about 0.2 g / L. In certain embodiments, the bulk density may range from about 0.05 g / L to about 0.15 g / mL or 0.10 g / L to about 0.15 g / L. In one embodiment, the specific surface area of ​​the microcrystalline complex particles of the spray-dried powder is about 30 m 2 / g~about 60m 2 / g.

[0067] In one embodiment, the compositions for delivery in an inhaler herein comprise fumaryl dihydrochloride. Ketopiperazine crystal particles or crystal complex particles and tetrahydrocannabinol (THC) and / or an active agent such as a cannabinoid, such as cannabidiol. In compositions in which cannabinoids are used as the active agent, their derivatives and / or analogues The cannabinoid content, including In some embodiments, the composition may be up to 40% (w / w) or more. The content of cannabinoids and / or other active agents in the composition is about 0.1% to 1.5% of the powder content. in the range of about 40 wt%, in the range of about 1% to about 30%, in the range of about 5% to about 25% (w / w), or The compositions herein may also contain, prior to spray drying, leucine, isoleucine, amino acids such as sucrine, methionine, and the like, and one or more phospholipids, e.g. For example, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) or 1, 2-distearoyl-sn-glycero-3-phosphocholine (DSPC), etc. The excipient may be present in an amount up to about 25% (w / w), in a range of about 1% (w / w) to about 25%, or in an amount of 2. It may be present in an amount ranging from 5% to 20% (w / w) or from 5% to 15% (w / w). In this embodiment, the inhaler can deliver up to 50 mg of the composition in a single inhalation. In this embodiment, the composition can excrete about 50% to 100% of the therapeutic The dose of the powder containing the active ingredient can be administered to a subject in need thereof as needed. , can be delivered in one or more inhalations via a dry powder inhaler.

[0068] In one embodiment, fumaryl diketopiperazine is used to improve the storage stability of the composition. crystalline complex particles of fumaryl diketopiperazine, leucine, isopropyl alcohol, and excipients such as amino acids such as leucine and methionine. In this embodiment, the inhalable cannabinoid composition can be administered to a patient. The composition is administered about 5 to 30 minutes, preferably about 5 to 15 minutes, before or at the same time as administering the therapeutic dose. The chemotherapy-induced pulmonary circulation can be prevented by self-administering the powder in a single inhalation using an inhaler containing a single dose of It can be used to prevent and treat nausea and vomiting induced by

[0069] In an alternative embodiment, the pharma- ceutical acceptable carrier for making the dry powder is The composition may include any carrier or excipient that is useful for making a dry powder and is suitable for pulmonary delivery. Examples of suitable carriers and excipients include monosaccharides and polysaccharides, such as lactose, mannose, Sugars such as sucrose, mannitol, and trehalose; citrate, glycine, L- Amino acids such as leucine, isoleucine, and trileucine, tartrate, methionine, and vitamin Vitamin A, Vitamin E, Zinc Citrate, Trisodium Citrate, Zinc Chloride, Polyvinylpyrrolate Lysine, polysorbate 80, diphosphotidylcholine phospholipids, such as phospholipids, phospholipids ... The pharmaceutical composition comprises a diketopiperazine.

[0070] In a further embodiment, a method for treating nausea, vomiting, and pain that may be associated with disease is disclosed. The method comprises administering to a patient in need of treatment, for example, a compound of the formula 2,5-diketo-3,6-di(4 -X-aminobutyl)piperazine, where X is succinyl, glutaryl, maleyl, and and fumaryl), and a cannabinoid In this embodiment, the method comprises administering an inhalable dry powder composition or formulation comprising: Thus, the dry powder composition is a pharmaceutical composition that can include a diketopiperazine salt. In an embodiment, a dry powder pharmaceutical composition or formulation is provided, the diketopiperazine being 2, 5-diketo-3,6-di-(4-fumaryl-aminobutyl)piperazine, With or without an acceptable carrier or excipient and a cannabinoid.

[0071] Exemplary cannabinoids include tetrahydrocannabinol (THC), cannabinoids, In certain embodiments, the pharmaceutical The composition comprises 3-6-bis(4-fumaryl-4-aminobutyl)-2,5-diketopiperazine. Tetrahydrocannabinol, cannabidiol, or cannabinol, or combination of these; and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DP PC) or 1,2-distearoyl-sn-glycero-3-phosphocholine, up to about 10 5 or up to about 15% (w / w) and, optionally, leucine, isoleucine, or methionine. In one embodiment, the pharmaceutical composition comprises mannitol, lactose, and other amino acids. The pharmaceutical composition may contain a surfactant such as polysorbate 80. , in the range of 0.05% to about 3% (w / w) of the total content of the composition, or in the range of about 1% to about 2% (w / In some embodiments, the composition may further comprise polyoxyethylene (PO) in an amount ranging from 0.1 to 1.0 w. Other pharma- ceutical acceptable salts such as polyvinylpyrrolidone, polyethylene gylycol, etc. The composition may contain about 0.5% to about 6% of a carrier and / or excipient.

[0072] An inhalation mechanism is provided for delivering a dry powder formulation to the lungs of a patient, the mechanism comprising a dosing arrangement The total airflow resistance is in the range of 0.055 to approximately 0.200 (√kPa) / liter per minute. The dry powder inhaler is configured to have a flow conduit with a value of

[0073] In one embodiment, a combination of the dry powder inhaler described above and a treatment for a disorder or disease, such as cancer or epilepsy, is provided. A pharmaceutical carrier containing one or more pharmaceuticals, including a dry powder formulation, for treating chronic pain resulting from a disease. A dry powder inhalation kit is provided comprising:

[0074] In one embodiment, a method for self-administering a dry powder formulation to the lungs using a dry powder inhalation mechanism. The method includes: taking a dry powder inhaler in a closed position and having a mouthpiece. and; disposing a cartridge containing a pre-metered dose of the dry powder formulation in a receiving arrangement. obtaining; opening the dry powder inhaler to install a cartridge; closing the inhaler to move the cartridge into a dosing position; and placing the mouthpiece in the mouth. and taking a single deep inhalation to deliver the dry powder formulation;

[0075] In this regard, the disclosed dry powder inhaler embodiments may be used to treat a disease or disorder in a patient. The method of treatment also includes administering to a patient in need of treatment a therapeutic agent selected from the group described above. The dosage of an inhalable formulation comprising the active ingredient and a pharma- ceutical acceptable carrier and / or excipient is providing a dry powder inhaler comprising a cartridge containing an inhalable formulation; To deliver the dose via a dry powder inhaler, have the patient inhale deeply for approximately 3-4 seconds. and administering the drug to the patient in a manner that allows the patient to subsequently undergo normal respiratory patterns. The session can then be resumed.

[0076] In one embodiment, the method provides for the relief of chronic pain, improvement of sleep, alleviation of neuropathy, and Patients in need of treatment for the reduction of anxiety and / or anxiety were given a combination of diketopiperazine and tetrahydrofuran. A cannabinoid selected from cannabinol, cannabidiol, and cannabinol. In one embodiment, the method further comprises administering an inhalable dry powder pharmaceutical composition comprising particles comprising In the present study, diketopiperazine is 3,6-bis(4-fumaryl-4-aminobutyl)-2 ,5-diketopiperazine.

[0077] In certain embodiments, a method for treating pain in a patient is provided, the method comprising: The patient is administered a dry powder inhaler and a medicinal dry powder inhaler containing a diketopiperazine and a cannabinoid. providing an inhalation mechanism comprising a dry powder composition; and administering said dry powder composition to said patient. and administering the dry powder to the patient by deep inhalation from said dry powder inhaler. The pharmaceutical composition may comprise one or more anti-inflammatory agents and other active agents, such as acetylsalicylic acid. The composition may further include acetaminophen, acetaminophen and its derivatives.

[0078] In an alternative embodiment, the inhalation mechanism comprises a dry powder inhaler and a dry powder composition. It comprises a drug delivery mechanism for inhalation; the dry powder composition comprises an antiviral or antibiotic compound. In one embodiment, the antiviral compound is used to treat respiratory infections or In certain embodiments, the antiviral compound is Selected from salicylates such as cetyl salicylate, curcumin, and / or vitamin C In one embodiment, the dry powder pharmaceutical composition comprises lactose, mannitol, trehalose, sugars such as fumaryl, xylitol; -Diketopiperazines and their derivatives; Citrates; Tartrates or other pharma- ceutical acceptable excipients and / or carriers. In one embodiment, the dry powder composition may comprise 3,6 -Bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine or a salt thereof, and Curcumin is included in powder amounts up to 50 mg by weight per dose.

[0079] In an exemplary embodiment, the dry powder composition comprises a diketopiperazine, e.g., a 3,6- (N-Fumaryl-4-aminobutyl)-2,5-diketopiperazine or its disodium salt A salt and curcumin, its analogues or derivatives, or a combination thereof, and optionally an acetonitrile. The composition contains 0.1 wt% to about 80 wt% or about 1 wt% to about 20 wt% of thyrsalicylic acid. In this embodiment, the dry powder composition may contain other pharma- ceutical acceptable excipients, e.g. phospholipids such as DSPC, DPPC and the like; mannitol, trehalose, lactose sugars such as titol, xylitol, etc.; leucine, isoleucine, methionine, glycine, etc. The amino acids may include those of various species.

[0080] A method for treating viral diseases, particularly respiratory tract and pulmonary infections, comprising administering to a subject in need of treatment For the subject, curcumin or its derivative is added to the dry powder pharmaceutical composition at a concentration of 0.5 wt% to Approximately 20 wt% of 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diamine A dry powder comprising particles of topiperazine and, optionally, one or more pharmaceutical excipients or carriers. In another embodiment, the method comprises administering a dry pharmaceutical composition in a therapeutic dose. The powder composition may further include a salicylate.

[0081] In one embodiment, a method for treating a viral infection, such as a retroviral infection, is provided. The method comprises: Diketopiperazines such as ketopiperazine and ribavirin, siRNA, acyclovir, amoxicillin, Intazin, foscarnet, glancyclovir, oseltamivir Mivir, Valacyclovir, Zidarabine, Zanamivir, Abacavir amprenavir, didanosine, indinavir, efavirenz, lamivudine, lopinavir vir, stavudine, nelfinavir, saquinavir ovir, zalcitabine, zidivudine, and the like and a dry powder inhaler comprising a pharmaceutical composition comprising one or more antiviral agents. The dry powder pharmaceutical composition may comprise one or more of the following: phospholipids, sugars, etc., as defined above. The composition may further comprise a variety of pharma- ceutically acceptable excipients and / or carriers.

[0082] In other embodiments, for prophylactic treatment or for the treatment of a respiratory disease in a subject. The method is 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-dikepiperazine ( dikepiperazine) particles and chloroquine, mefloquine, primaquine, tafe Quinine, such as hydroxychloroquine or its salts (e.g., hydroxychloroquine sulfate) Derivatives and their salts; one or more active substances such as acetylsalicylic acid, its analogues or derivatives, etc. and one or more pharma- ceutical acceptable excipients. The active ingredient may be administered in a single dose or multiple doses in a therapeutic amount to a subject in need thereof. It can be delivered by oral inhalation using a single-use breath-actuated dry powder inhaler. The composition may be presented in a capsule or cartridge.

[0083] In an alternative embodiment, a method of treating respiratory tract and pulmonary infections is provided, the method comprising: A subject in need of treatment is administered a dry powder inhaler, a diketopiperazine, and one or more active ingredients. an antibacterial agent and one or more pharma- ceutical acceptable excipients; an antibiotic, an antiviral, an antiviral and an active agent, such as an inflammatory agent, an antiasthmatic agent, or a combination thereof. In one embodiment, the antibiotic is azithromycin. tobramycin, doxycycline, minocycline, tetracycline, ciprofloxacin, Ciproflaxin, amoxicillin, penicillin, ceftin, ceftidine Riaxone, cephalexin, fosfomycin, clindamycin, levofloxacin, Nalidixic acid, nitrofurantoin, tgrimethoprim / Sulfamethoxazole, Rifampicin, Gentamicin, Trimethoprim, Methotrexate Nidazole, ceftolozane, tazobactam, imipenem, cilastatin, relebactam and and the like. In some embodiments, the anti-asthma agent is , long-acting and short-acting formoterol, fluticasone, budesonide, mometasone beclomethasone, ciclesonide, albuterol, ipratropium, theofilipin B-agonists such as levalbuterol and prednisone, methylprednisolone, etc. In this and other embodiments, the diketopy Perazine has the formula: [ka] or a salt thereof, in particular the disodium or magnesium salt; The radicin may be in the form of a pharmaceutical dry crystalline powder, an amorphous powder or a microcrystalline powder suitable for inhalation. The medicinal dry powder is administered to a patient in need thereof using a dry powder inhaler. A maximum of 50 mg per dose is administered in a single inhalation. In one embodiment, the dry powder The dose or doses of the medicament may be administered either individually as each active agent or in any combination thereof. Powders can also be administered in a single dose with one or more active agents. In embodiments where the dry powder contains a single active agent, the patient may be In some embodiments, one dose of each powder may be administered sequentially as needed. Thus, the dry powder can be prepared to contain more than one active agent for treating a disease. and the patient can be administered one or more doses of the dry powder combination. do.

[0084] The following examples illustrate dry powders suitable for use with the inhalers described herein. Illustrates the process for making and some of the data obtained from experiments using dry powders. It is something. EXAMPLES

[0085] Example 1 Surfactant-free dry powders containing FDKP microcrystalline powder for use with inhalers: In an exemplary embodiment, a surfactant-free dry powder comprising FDKP microcrystalline particles is prepared. A dual-feed high shear mixer was used to mix approximately equal masses of F The DKP solution (Table 1) and acetic acid solution (Table 2) were kept at approximately 25°C ± 5°C and heated at 2000 psi. Homogenization through a 0.001-in2 orifice A precipitate was formed by the addition of water. The precipitate was collected in deionized (DI) water of approximately the same temperature. The content (wt%) of FDKP microcrystals in the suspension is about 2-3.5%. The KP concentration can be evaluated in terms of solids by the oven drying method. The crystal suspension is optionally washed with deionized water by tangential flow filtration. The FDKP microcrystals can be optionally filtered, centrifuged, spray-dried, or freeze-dried. It can be isolated from

[0086] [Table 1]

[0087] [Table 2]

[0088] Dry powders (A, B, C, and D) containing microcrystalline particles prepared by the method described above It was tested for a variety of properties, including measurements of surface area, moisture content, and pore characteristics. Four different powders were used in this experiment. All the powders tested had a residual moisture content of The result was 0.4%. Table 3 shows the data from this experiment.

[0089] [Table 3]

[0090] The data in Table 3 are for the spray-dried bulk dry powders containing microcrystalline particles of the samples tested. The final surface area is 59 m 2 / g~63m 2 / g. The data show that the microcrystalline particles are relatively porous, with the average pore volume measured by BJH adsorption. is about 0.43 cm 3 / g, and the average pore size is in the range of about 23.8 nm to 26.2 nm. In certain sample embodiments, the particles have pore sizes up to 30 nm. Porosimetry data indicate that these particles have an average pore volume of approximately 0.36 cm 3 / g, and the average pore size is about 20 nm to about 22.6 nm. This indicates that the FDKP particles are different from those of the FDKP particles of the

[0091] Example 2 Preparation of dry powders containing FDKP microcrystalline particles containing Δ9-THC or CBD. The FDKP microcrystalline particles prepared according to 1 were isolated and suspended in ethyl alcohol. Approximately 1-4 wt% ethanol of cannabis extract containing either Δ9-THC or CBD The solution and an ethanolic suspension of FDKP microcrystals were added. Optionally, the additive was added in ethanol. The mixture was sprayed using a Buchi B290 sprayer equipped with a highly efficient cyclone. The mixture was spray dried using a fog dryer. Nitrogen was used as the process gas (60 mm). The pump capacity is 12-15%, the suction speed is 70-100%, and the inlet temperature is 110-140℃. The concentrations (wt%) of Δ9-THC and additional additives are shown in Table 4. The delivery efficiency of these powders after being expelled from the injector ranged from approximately 50% to 70%.

[0092] [Table 4]

[0093] The dry powder produced by the method described above was prepared according to the method described in U.S. Pat. No. 9,016,147. Dry powder was tested using the anatomically accurate airway (ACA) system described in. The powder exhibits extremely high stability at room temperature, for example, no THC or CBD was detected after one month of storage. More than 90% of the active compound remains active, and the delivery efficiency using this method is about 35% to about 75%. was in the range.

[0094] Table 5 shows data for three replicates of a sample of the formulation. As described above, the cannabinoid TH Formulations containing up to 30% C were prepared with the crystalline complex FDKP particles and various excipient components shown here. Both powder samples were prepared and tested on the ACA system. Powder samples were either manually filled or The cartridges were either filled using the ot system or dried. The samples were tested using a dry powder inhaler (MannKind Corp.). The data are shown in Table 5.

[0095] [Table 5] CE indicates that the cartridge has been emptied or that the entire powder content released during the test of the batch has been discharged. The percentage of the body is shown. Blank cells indicate that the powder was not tested.

[0096] The data show that the CE values ​​obtained are consistent with the release of up to 99.5% of the total powder contents in the inhaler. The results show that powders made with various excipients have excellent aerodynamic properties. Therefore, the powder containing the surfactant PS80 has the following characteristics: The delivery rate (%) of the powder contents was up to 72% except for the pulmonary The formulation containing PS80 was able to deliver the drug effectively. The powders produced in this connection were observed to have a powder batch size of 1000 mm or less at the time of powder production. The cannabinoid content was measured at this point, as well as 2 and 4 weeks after powder production (stored at room temperature). The data shown in Table 6 are based on the powder. Cannabinoid content of various cannabinoid preparations obtained from the final samples up to 4 weeks It indicates quantity.

[0097] [Table 6]

[0098] The data in Table 6 indicates that the powder formulations produced were stored for at least 4 weeks before testing. The results indicate that the samples are very stable at room temperature for periods of 10-20 min, with some samples potentially being stable for longer. vinegar.

[0099] The above disclosure is illustrative of the embodiments. It is understood that those skilled in the art will recognize that exemplary embodiments function satisfactorily in practicing the present disclosure. However, those skilled in the art will be able to understand the spirit and scope of the present invention in light of this disclosure. Many changes may be made to the specific embodiments disclosed without departing from the scope of the present invention. It should be understood that this is possible and the same or similar results would still be obtained.

[0100] Unless otherwise specified, the amounts, proportions and other information of ingredients used in this specification and claims are All numerical values ​​expressing properties such as molecular weights, reaction conditions, etc. are expressly intended to be understood as being approximately Therefore, unless otherwise indicated, Therefore, the numerical parameters set forth in the following specification and appended claims are within the limits of what can be achieved. These are approximations that may vary depending on the desired properties. Without intending to limit the application of the doctrine of equivalents, each numerical parameter should at least be considered as being within the limits of the reported should be interpreted in light of the number of significant digits given and by applying ordinary rounding techniques. Although the numerical ranges and parameters set forth are approximations, the numerical values ​​set forth in the specific examples are within the scope of the present invention. Value ranges are reported as precisely as possible; however, any values ​​may vary depending on the measurements of each study. These data inherently contain certain errors necessarily resulting from the standard deviation found in the determination of experimental data.

[0101] The words "a," "an," and "the" and similar demonstrative pronouns are used herein. Unless otherwise specified or clearly contradicted by context, both the singular and plural forms are used. The recitation of ranges of values ​​herein merely includes any number of values ​​within that range. It is intended to serve as a shorthand method of referring to each separate value individually. Unless otherwise specified in the document, each individual value is individually listed herein. All methods described herein are incorporated by reference in their entirety. Unless otherwise specified in the document or clearly contradicted by the context, Any examples or exemplary expressions provided herein may be implemented in any order. (eg, "etc.") is intended merely to make the invention clearer, and in particular Unless otherwise claimed, no limitation is intended. Nothing in the claims should be construed as indicating any non-claimed element essential to the practice of the invention. There is none.

[0102] Use of the word "or" in the claims refers to alternatives only or to all alternatives. Used to mean "and / or" unless expressly stated to be mutually exclusive. Although the terms "and" and "and / or" are used interchangeably herein, the disclosure is directed to the definition referring only to alternatives and to "and / or." Hold.

[0103] Groupings of alternative elements or embodiments disclosed herein are not to be construed as limitations. Each group member may be used individually or in combination with other members of the group or other members found herein. Any combination of any one of the elements of a group may be referred to or claimed. Although one or more elements may be included in a group for reasons of convenience and / or patentability, It is also anticipated that such inclusion or exclusion may occur. In this case, the specification is deemed to include the group as so modified and accordingly the appended claims. It satisfies any Markush group description used in the claims.

[0104]

[0023] There are herein described specific embodiments for carrying out the invention, including the best mode known to the inventors. Of course, variations of these preferred embodiments are possible. Such embodiments will be apparent to those of skill in the art upon reading the above description. It is anticipated that those skilled in the art will employ such modifications as necessary, and the inventors will It is intended that the invention be practiced other than as specifically described herein. Accordingly, the present invention relates to the application of the subject matter recited in the claims appended hereto. In addition, any and all modifications and equivalents of the elements set forth above are included. Any combination of the possible variations is contemplated herein unless otherwise specified or incorporated in the text. Unless clearly inconsistent with the present context, they are encompassed by the present invention.

[0105] Specific embodiments disclosed herein may be described in the claims as "consisting of" or " The claims may be further limited using the phrase "consisting essentially of." When using the term, whether originally filed or added following an amendment, the term "consisting of The transitional phrase " " refers to any element, step, or "Consisting essentially of" excludes the components specified. and limiting the scope of the claims to those that do not materially affect the basic and novel characteristics. The embodiments described herein are inherently or explicitly described and are considered valid.

[0106] Additionally, numerous patents and publications have been referenced throughout this specification. Each of the documents and publications is individually incorporated by reference herein in its entirety.

[0107] It is further understood that the embodiments disclosed herein are illustrative of the principles of the present invention. Other modifications that may be used are within the scope of the present invention. As an indication, alternative configurations may be utilized in accordance with the teachings herein. Therefore, the present invention is not limited to that precisely as shown and described.

Claims

1. 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine and 1. A dry powder pharmaceutical composition comprising microcrystalline particles of a cannabinoid; is 1%-40% (w / w) of the total weight of the composition.

2. The cannabinoids may be one or more of tetrahydrocannabinol, cannabidiol, 2. The dry powder of claim 1, wherein the dry powder is selected from the group consisting of ethanol, cannabinol, and combinations thereof. Pharmaceutical compositions.

3. The dry powder comprises 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1 , 2-distearoyl-sn-glycero-3-phosphocholine; 2. The dry powder pharmaceutical composition of claim 1, comprising:

4. The microcrystalline particles have an average pore volume of about 0.36 cm ３ / g ~ approx. 0.43cm ３ / g The dry powder pharmaceutical composition of claim 1 .

5. 2. The dry sieve of claim 1, wherein the microcrystalline particles have an average pore size of about 23 nm to about 28 nm. A dry powder pharmaceutical composition.

6. The microcrystalline particles have a surface area of ​​approximately 59 m ２ / g ~ approx. 63m ２ / g range according to claim 1. The dry powder pharmaceutical composition described above.

7. The microcrystalline particles have an average pore volume of about 0.43 cm as measured by BJH adsorption. ３ / g and the average pore size is in the range of about 23.8 nm to 26.2 nm. A dry powder pharmaceutical composition.

8. A dry powder inhaler comprising a dry powder pharmaceutical composition comprising tetrahydrocannabinol, cannabinol, cannabidiol or cannabinol is 1% to about 40% (w / w) of the total content of the dry powder. w) in an amount of 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopy A dry powder inhaler containing microcrystalline particles of perazine.

9. The dry powder comprises 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1 , 2-distearoyl-sn-glycero-3-phosphocholine; 10. The dry powder inhaler of claim 8, further comprising: 。

10. A method for treating chronic pain comprising administering to a patient in need of treatment a therapeutically effective amount of The dry powder pharmaceutical composition according to the present invention is administered by oral inhalation using a dry powder inhaler. Hmm, a method.

11. 1. A dry powder drug delivery system comprising a dry powder inhaler containing a dry powder pharmaceutical composition comprising 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine and microcrystalline particles of a cannabinoid; wherein the amount of said cannabinoid is 1% to 40% (w / w) of the total weight of said composition, and said microcrystalline particles have an average pore volume of about 0.43 cm3 / g and an average pore diameter in the range of about 23.8 nm to 26.2 nm as measured by BJH adsorption.

Images