Methods and devices for generating core-shell droplets and particles

Abstract

A simple and cost-effective technique for generating high-throughput aerosols of sub-millimeter-sized core-shell particles with a uniform diameter is disclosed. The aerosol can be created, for example, by using a first tube filled with a liquid and having small holes penetrating the sidewalls, and then passing a fluid through the liquid via a second tube that partially passes through the first tube at a position above the small holes to form a coaxial flow through the small holes. The diameter of the generated core-shell particles is proportional to the inner and outer diameters of the gas tube nozzle, and the size of the generated particles can be controlled. Further, a simple, scalable, and cost-effective technique is disclosed that enables the microencapsulation of various substances. Particles of 10 pm or less are made, including high-viscosity materials. A specially designed atomizing tube interacts with bubbles formed in a liquid containing multiple immiscible liquid layers to generate an aerosol of droplets having a layered core-shell structure.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims priority to U.S. Provisional Patent Application No. 63 / 349,378, filed on June 6, 2022, and U.S. Provisional Patent Application No. 63 / 358,397, filed on July 5, 2022, each of which is hereby incorporated by reference in its entirety.

[0002] This disclosure relates to techniques for forming core - shell droplets and particles.

Background Art

[0003] Aerosols having core - shell particles have many applications, such as, for example, direct delivery of substances in medical applications (e.g., delivery to the nose or throat), use of core - shell particles for ultrasonic diagnosis, encapsulation of substances for storage, protection, and controlled release, manufacture of foams, additive manufacturing, food manufacturing, and entertainment applications. However, there is no technology for forming aerosols that can meet the requirements of such applications. For example, in the prior art, it is not possible to produce substantially uniform droplets and particle sizes with a simple system or device at a reasonable cost and high production rate.

Summary of the Invention

Means for Solving the Problems

[0004] The devices, systems, and techniques of this disclosure overcome the disadvantages of the prior art.

[0005] In various aspects, a device for generating substantially uniform core-shell particles can be provided. For simplicity, in this application, "particle" is used in a broad sense and includes solid or semi-solid particles, droplets, etc. Such particles can be dispersed in a gaseous fluid, i.e., as an aerosol. The device can include a first tubular member and at least one second tubular member. The first tubular member can have a first end and a second end. The first tubular member can have a first inner lumen and at least one second inner lumen. The first inner lumen can extend from the first end to the second end. Each second inner lumen extends from the outer surface of the first tubular member through the side wall of the first tubular member and can connect to the first inner lumen at a position axially at a distance (which can be a predetermined distance) from any end (e.g., from the first end). At least one second tubular member (which can be a needle, for example) can have a first end disposed outside the first tubular member and a second end within the first inner lumen and directed towards one of the at least one second inner lumen. At least one second tubular member can extend through the side wall of the first tubular member. At least one second tubular member can have an annular cross-sectional shape defined by an inner diameter and a wall thickness.

[0006] In this arrangement, during operation, the fluid flowing through the second tubular member exits from the second end of the second tubular member, flows through the fluid within the first tubular member, and exits out through the second inner lumen. The particles include a "core" formed from the fluid flowing through the second tubular member, and the core is surrounded by a "shell" formed from the fluid flowing through the first tubular member.

[0007] The device can include one or more connectors. Each connector can be operably coupled to the first end of the first tubular member, the second end of the first tubular member, or one of the first ends of the at least one second tubular member.

[0008] The first tubular member can be composed of an elastic material. When pressurized liquid is supplied to the first inner lumen, at least one second inner lumen can open or expand.

[0009] At least one second tubular member may be composed of a rigid material. The at least one second tubular member may have an inner diameter D where 10 μm < D < 1 mm and a wall thickness T where 10 μm < T < 1 mm.

[0010] The device may include a single second lumen and a single second tubular member. The device may include a plurality of second lumens and a plurality of second tubular members, each of which is directed towards one of the plurality of second lumens. Preferably, the number of second lumens is equal to the number of second tubular members.

[0011] The device may include at least one third tubular member having an inner diameter greater than the outer diameter of the first tubular member. The first tubular member and the at least one third tubular member may be positioned concentrically and are configured to produce core-shell particles having a plurality of shells around a core.

[0012] The at least one third tubular member may have at least one third lumen positioned such that particles exiting the at least one second lumen also pass through the at least one third lumen. In this arrangement, the innermost layer of the shell around the core is formed from the fluid flowing through the first tubular member, and the outermost layer(s) of the shell is / are formed from the fluid flowing through the third tubular member(s).

[0013] The device may include at least one fourth tubular member having an inner diameter greater than the outer diameter of the at least one second tubular member. The at least one second tubular member and the at least one fourth tubular member may be positioned concentrically and are configured to produce a core composed of a plurality of materials.

[0014] In various aspects, a system can be provided. The system can include a device for generating substantially uniform core-shell particles as disclosed herein. The system can include a first fluid source operably coupled to a first end of a first tubular member, the first fluid source being configured to supply a first fluid. The system can include a second fluid source operably coupled to a first end of at least one second tubular member, the second fluid source being configured to supply a second fluid. In some embodiments, the first fluid is a liquid and the second fluid is a gas. In some embodiments, the first fluid and the second fluid are different liquids. In some embodiments, the first fluid and the second fluid do not include a surfactant.

[0015] The system can include a container for collecting core-shell particles that move along a path extending in a direction away from the second lumen. The system can include at least one controller for controlling the flow of fluid through the device such that core-shell particles can be formed and directed from at least one second lumen. The system can include drying means, photopolymerization means, or pyrolysis means, operably coupled to the controller(s). The drying, photopolymerization, or pyrolysis means can be configured to convert at least one layer of the core-shell particles formed by the device from a liquid to a solid. The core-shell particles can be converted into (or as) an aerosol. The core-shell particles can be converted at the surface.

[0016] In various aspects, a kit can be provided. The kit can include a device for generating substantially uniform core-shell particles as disclosed herein. The kit can include drying means and / or photopolymerization means.

[0017] In various aspects, a method for generating substantially uniform core-shell particles can be provided. The method can include supplying a first fluid to a first lumen of a device for generating substantially uniform core-shell particles as disclosed herein. The pressure of the first fluid can open a second lumen and form a fluid film that spreads into the opened second lumen. The method can include generating substantially uniform core-shell particles by supplying a second fluid to a second tubular member. The second tubular member can be configured to direct the second fluid through the fluid film, such that core-shell particles having a shell of the first fluid surrounding a core containing the second fluid are formed. The first fluid and the second fluid may not contain a surfactant.

[0018] The method can include passing at least one additional fluid through at least one additional tubular member concentrically disposed around the second tubular member to produce single-shell spheres having a multi-material core of gas, liquid, or a combination thereof.

[0019] The method can include passing the core-shell particles through one additional fluid stream passing through at least one tubular member concentrically disposed around the first tubular member to produce multi-shell spheres around a core of gas or liquid.

[0020] The method can include drying the core-shell particles. The method can include photopolymerizing the shell and / or the core of the core-shell particles. The method can include pyrolyzing the core-shell particles. The method can include causing a chemical reaction in at least one layer of the core-shell particles. The method can include collecting the core-shell particles. The method can include foaming the core-shell particles.

[0021] In various embodiments, each core-shell particle may include, hereinafter, (i) a microsphere having a single layer of fluid shell and a fluid core of one material, (ii) a microsphere having a multi-layer fluid shell and a fluid core of one material, (iii) a microsphere having a single layer of fluid shell and a multi-material fluid core, or (iv) a microsphere having a multi-layer fluid shell and a multi-material fluid core.

[0022] The fluid shell may include a liquid. The fluid shell may include a solid. The fluid core may include a gas. The fluid core may include a liquid. The fluid core may include a solid.

[0023] The method may include adjusting the pressure of a first fluid to control the outlet area of a second lumen. The method may include adjusting the pressure of the first fluid to control the size of the core-shell particles.

[0024] The second tubular member, the first lumen, and the pressure of the first fluid may be configured to provide core-shell particles having an outer diameter of about 200 microns or less. At least 10 mL / min of core-shell particles may pass through a single second lumen.

[0025] In various aspects, an alternative system may be provided, which is configured to produce particles containing micron-sized droplets, sub-micron-sized droplets, or microencapsulated materials. The system may include an atomization (or "aerosolization") chamber. The system may include a tube within the atomization chamber. The tube may be configured to be partially immersed in a liquid. The tube may include an opening through the sidewall of the tube, and the opening is arranged such that at least some of the openings are configured to direct a gas jet towards bubbles on the surface of the liquid to form particles containing micron-sized droplets, sub-micron-sized droplets, or microencapsulated materials. The liquid may include a plurality of immiscible liquid layers.

[0026] The plurality of immiscible liquid layers may include a first layer containing a first material R, a second layer containing a second material G, and a third material B in the first layer and / or the second layer, where R, G, and B are selected such that γRB > γRG + γGB, γRB is the interfacial surface tension between materials R and B, γRG is the interfacial surface tension between materials R and G, and γGB is the interfacial surface tension between materials G and B.

[0027] Particles containing micron-sized droplets, sub-micron-sized droplets, or microencapsulated substances may include a single-layer shell. Droplets or particles having a single-layer shell may include a single-material core. Droplets or particles having a single-layer shell may include a multi-material core. Particles containing micron-sized droplets, sub-micron-sized droplets, or microencapsulated substances include a multi-layer shell. Droplets or particles having a multi-layer shell may include a single-material core. Droplets or particles having a multi-layer shell may include a multi-material core. In some embodiments, all the shells may be liquid or solid, or one or more shells may be liquid and one or more shells may be solid. In some embodiments, the core may be liquid or solid, or the core may include a mixture of solid and liquid materials.

[0028] The system may include a guide tube coupled to the top of the atomization chamber. The guide tube may be ultraviolet (UV) transmissive. The guide tube may be configured to have a heated wall, an insulated wall, or a cooled wall. The guide tube may include a bottom coupled to the atomization chamber. The bottom and / or sidewalls of the guide tube may be configured to have openings for entraining external ambient gas for mixing with the aerosol within the guide tube.

[0029] The system may include an ultraviolet (UV) light source configured to irradiate an aerosol within a guide tube. The system may include an electrically heated or cooled coil coupled to the guide tube. The system may include a parabolic mirror configured to collect solar energy for irradiating the guide tube. The system may include a burner coupled to an end of the guide tube, the burner being configured to solidify, dehydrate, or pyrolyze aerosol droplets. The system may include at least one chamber configured to form a dry particle aerosol via evaporation of a solvent of a submicron droplet aerosol. The system may include a particle collector configured to collect dry particles from the dry particle aerosol. The system may include a liquid, solid, or electrostatic filter for capturing particulate matter from an aerosol stream flowing within the guide tube.

[0030] In various aspects, a method of generating particles containing micron-sized droplets, submicron-sized droplets, or encapsulated materials may be provided. The method includes providing a liquid including a plurality of immiscible liquid layers. The method may include aerating the liquid within an atomization chamber such that bubbles rise to the surface of the liquid to form bubbles passing through each of the plurality of immiscible liquid layers. The method may include forming a submicron droplet aerosol by directing a gas jet through an opening of a tube toward at least one of the bubbles within the atomization chamber.

[0031] The method may include heating or cooling a guide tube coupled to the upper part of the atomization chamber. The method may include entraining external ambient gas through an opening of a part of the guide tube coupled to the side wall of the atomization chamber and / or the guide tube, and mixing it with the aerosol in the guide tube. The method may include photopolymerizing the material in the bubbles by irradiating ultraviolet (UV) light toward the aerosol in the guide tube. The method may include solidifying, dehydrating, and pyrolyzing the aerosol droplets. The method may include forming dry particle aerosol through solvent evaporation of submicron droplet aerosol. The method may include forming a powder of submicron or nanostructured particles by passing the dry particle aerosol through a particle collector.

[0032] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and, together with the general description of the invention given above and the detailed description of the embodiments given below, serve to explain the principles of the invention.

Brief Description of the Drawings

[0033]

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[0034] It should be understood that the accompanying drawings are not necessarily to scale and represent somewhat simplified illustrations of various features exemplifying the basic principles of the invention. For example, specific design features of a series of operations disclosed herein, such as the specific dimensions, orientations, positions, shapes, etc. of various illustrated components, are in part determined by the particular intended use and operating environment. Certain features of the illustrated embodiments are enlarged or distorted relative to others for ease of visualization and clear understanding. In particular, for example, thin features may be represented thicker for clarity or explanation.

[0035] The following description and drawings merely explain the principles of the present invention. Accordingly, those skilled in the art will understand that, although not explicitly described or shown herein, various modifications that embody the principles of the present invention and fall within the scope of the present invention can be devised. Further, all examples cited in this specification are clearly intended solely for illustrative purposes to assist the reader in understanding the principles of the present invention and the concepts provided by the inventor(s) for further advancement of the art, and are not to be construed as being limited to such specifically cited examples and conditions. Further, as used herein, the term "or" means non-exclusive "or" (e.g., "or, alternatively", or "or, additionally") unless otherwise indicated. Also, since some embodiments can be combined with one or more other embodiments to form new embodiments, the various embodiments described herein are not necessarily mutually exclusive.

[0036] Numerous innovative teachings of this application are described with particular reference to presently preferred exemplary embodiments. However, it should be understood that such embodiments merely provide a few examples of many advantageous uses of the innovative teachings herein. In general, the descriptions made in the specification of this application do not necessarily limit the various inventions claimed. Further, some descriptions may apply to certain inventive features but not to others. Those skilled in the art and knowledgeable from the teachings herein will understand that the present invention is applicable to various other technical fields or embodiments.

[0037] In various aspects, a device for generating substantially uniform core-shell particles can be provided. Referring to FIGS. 1-3, the device 100 can include a first tubular member 110 and at least one second tubular member 120.

[0038] The first tubular member 110 may have a first end 111 and a second end 112 axially spaced from the first end. The first tubular member may have a first inner cavity 113 and at least one second inner cavity 114. The first inner cavity 113 may extend from the first end to the second end. Each second inner cavity 114 may extend from the outer surface 115 of the first tubular member 110, through the side wall 116 of the first tubular member 110, and connect to the first inner cavity 113 at a position axially at a distance 117 (which may be a predetermined distance) from any end (e.g., from the first end).

[0039] The first tubular member 110 may have a first fluid 130 flowing therethrough. In some embodiments, some or all of the first fluid 130 may flow from the first end towards the second end. In some embodiments, some or all of the first fluid 130 may flow from the second end towards the first end. In some embodiments, the fluid flowing from the first end may flow around the second tubular member 120 and enter the second inner cavity 114. In some embodiments, the fluid flowing from the first end may flow around the second tubular member 120 and enter the second inner cavity 114. The first fluid 130 entering the second inner cavity 114 may form a surface 133 that extends radially outward from the outer surface 115 of the first tubular member 110 within the second inner cavity 114.

[0040] The first tubular member 110 may be composed of a rigid material. For example, the tubular member may be composed of polyvinyl chloride or stainless steel.

[0041] The first tubular member 110 may be composed of an elastic material or an expandable material. For example, the tubular member may be composed of latex or natural rubber. At least one second inner cavity 114 may open or expand when a pressurized liquid is supplied to the first inner cavity 113.

[0042] The first tubular member 110 may be composed of a polymer, such as polyethylene, polypropylene, or polyurethane.

[0043] The first tubular member 110 may have an inner diameter (D1) 201 of 10 μm < D1 < 10 mm and a wall thickness (T1) 202 of 10 μm < T1 < 5 mm, defined by the first inner cavity 113. In some embodiments, D1 may be 50 mm or less. In some embodiments, D1 may be 40 mm or less. In some embodiments, D1 may be 30 mm or less. In some embodiments, D1 may be 20 mm or less. In some embodiments, D1 may be 10 mm or less. In some embodiments, D1 may be 5 mm or less. In some embodiments, D1 may be 3 mm or less. In some embodiments, T1 may be 10 mm or less. In some embodiments, T1 may be 5 mm or less. In some embodiments, T1 may be 3 mm or less. In some embodiments, T1 may be 2 mm or less. In some embodiments, T1 may be 1 mm or less.

[0044] It should be noted that as used herein, the term "diameter" is intended to refer to the greatest separation within the inner cavity between two opposing surfaces through which the fluid of interest flows. In the case of an inner cavity with a circular cross-section, this is the inner cavity diameter. In the case of an inner cavity with a rectangular cross-section (for example), this is the greater of the length or width of the rectangle.

[0045] The cross-section of the inner cavity can be various. In some embodiments, the first inner cavity 113 may have a circular cross-section. In some embodiments, the first inner cavity 113 may have a rectangular cross-section. In some embodiments, the first inner cavity 113 may have an elliptical cross-section.

[0046] At least one second inner cavity 114 may have an inner diameter (D2) 203 of 20 μm < D2 < 5 mm. In some embodiments, D2 may be 5 mm or less. In some embodiments, D2 may be 4 mm or less. In some embodiments, D2 may be 3 mm or less. D2 may be 4 mm or less. In some embodiments, D2 may be 2 mm or less.

[0047] At least one second tubular member 120 (which can be, for example, a needle) has a first end 121 positioned or disposed outside the first tubular member 110, and a second end 122 positioned or disposed within the first lumen 113 and directed towards one of at least one second lumen 114. In other words, the second end must be configured such that a second fluid 140 passing through the second tubular member passes through the second lumen 114 towards which the second end is directed. At least one second tubular member 120 can extend through the side wall of the first tubular member 110. At least one second tubular member 120 can have an annular cross-sectional shape defined by an inner diameter and a wall thickness.

[0048] In this arrangement, during operation, a second fluid 140 flowing (141) through the second tubular member 120 exits from the second end 122 of the second tubular member 120 and forms a base "core" 151 flowing through the first fluid 130 within the second lumen 114 of the first tubular member 110, and then exits through the second lumen 114 to form individual particles 150 containing the core 151 and an outer "shell" 152 formed from the first fluid 130.

[0049] At least one second tubular member 120 can be composed of a rigid material. The rigid material can be, for example, stainless steel, glass, etc. As used herein, the term "rigid" refers to a component having a substantially hard structure that resists bending and is generally not flexible.

[0050] At least one second tubular member 120 can have an inner diameter (D) 301 where 10 μm < D < 1 mm and a wall thickness (T) 302 where 10 μm < T < 1 mm. In some embodiments, the second lumen 114 can have an inner diameter (D2) that is at least 1 mm larger than the inner diameter D of the second tubular member 120. In some embodiments, D2 can be at least 2 mm larger than the inner diameter D of the second tubular member 120. In some embodiments, D2 can be at least twice the size of the inner diameter D of the second tubular member 120.

[0051] Since the disclosed process involves the flow of liquid through the pores of the elastic tube, the viscosity of the liquid is one of the limiting factors. Another limitation is the hydraulic pressure that can be maintained without rupturing the elastic tube material. Also, the diameter of the particles produced depends at least in part on the inner and outer diameters of the second tubular member 120, thereby limiting the minimum achievable diameter of the produced particles. Specifically, due to the latter limitation, when a prototype using a 34-gauge stainless steel blunt needle with an inner diameter of 83 μm and an outer diameter of 184 μm was tested, a minimum diameter of 200 μm was obtained for the produced uniform-sized core-shell particles. As a result, this device may require a second tubular member 120 having an outer diameter smaller than the desired target diameter of the core-shell particles. In some embodiments, the outer diameter can be 80-99% of the target diameter of the core-shell particles. In some embodiments, the outer diameter can be 85-97% of the target diameter of the core-shell particles. In some embodiments, the outer diameter can be 90-95% of the target diameter of the core-shell particles.

[0052] In some embodiments, the various fluids used to form droplets, particles, etc. comprise, consist of, or consist essentially of one or more solvents. In some embodiments, the various fluids used to form droplets, particles, etc. comprise, consist of, or consist essentially of one or more dispersed active chemical or biological substances.

[0053] Active chemical or biological substance The active chemical or biological substance can be any suitable substance as would be understood by one of ordinary skill in the art, depending on the purpose of the aerosol.

[0054] Examples of active chemicals can include, for example, nutraceuticals, pharmaceuticals, and / or supplements.

[0055] For example, any drug, pharmaceutically acceptable salt of a drug, drug derivative, drug analog, drug homolog, or polymorph may be used in the present invention. Suitable agents for use in the present invention can be found in the Physician’s Desk Reference, 71st Edition, the content of which is incorporated herein by reference.

[0056] In certain embodiments, psychoactive drugs and analgesics can be used, including but not limited to opioids, narcotics, stimulants, tranquilizers, sedatives, anti-anxiety agents, anesthetics, and drugs that can cause psychological and / or physical dependence. In one embodiment, drugs for use in the present invention can include amphetamine, amphetamine-like compounds, benzodiazepines, and methyl phenidate, or combinations thereof. In another embodiment, the drug can include any of the diastereoisomers of the drugs described herein and / or salts thereof.

[0057] Other non-limiting drugs that can be used include alfentanil, amphetamine, buprenorphine, butorphanol, carfentanil, codeine, desocine, diacetylmorphine, dihydrocodeine, dihydromorphine, diphenoxylate, diprenorphine, etorphine, fentanyl, hydrocodone, hydromorphone, β-hydroxy-3-methylfentanyl, levo-α-acetylmethadol, levorphanol, lofentanil, meperidine, methadone, methylphenidate, morphine, nalbuphine, nalmefene, oxycodone, oxymorphone, pentazocine, pethidine, propoxyphene, remifentanil, sufentanil, tilidine, and tramadol, their salts, derivatives, analogs, homologs, polymorphs, and mixtures of any of the foregoing.

[0058] Further non-limiting examples of chemicals that can be used include dextromethorphan (3-methoxy-17-methyl-9a,13a,14a-morphinan hydrobromide monohydrate), N-{1-[2-(4-ethyl-5-oxo-2-tetrazolin-1-yl)-ethyl]-4-methoxymethyl-4-piperidyl} propionanilide (alfentanil), 5,5-diallylbarbituric acid (allobarbital), allylprodine, α-prodine, 8-chloro-1-methyl-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]-benzodiazepine (alprazolam), 2-diethylaminopropiophenone (amfepramone), (±)-α-methylphenethylamine (amphetamine), 2-(α-methylphenethyl-amino)-2-phenylacetonitrile (amphetaminyl), 5-ethyl-5-isopentylbarbituric acid (amobarbital), anileridine, apocodeine, 5,5-diethylbarbituric acid (barbital), benzylmorphine, bezitramide, 7-bromo-5-(2-pyridyl)-1H-1,4-benzodiazepin-2(3H)-one (bromazepam), 2-bromo-4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]-triazolo[4,3-a][1,4]diazepine (brotizolam), 17-cyclopropylmethyl-4,5α-epoxy-7α[(S)-1-hydroxy-1,2,2-trimethylpropyl]-6-methoxy-6,14-end-ethanomorphinan-3-ol (buprenorphine), 5-butyl-5-ethylbarbituric acid (butabarbital), butorphanol, (7-chloro-1,3-dihydro-1-methyl-2-oxo-5-phenyl-2H-1,4-benzodiazepin-3-yl)-dimethylcarbamate (carbamazepam), (1S,2S)-2-amino-1-phenyl-1-propanol (cathin / D-norpsuedoephedrine), 7-chloro-N-methyl-5-phenyl-3H-1,4-benzodiazepin-2-ylamine-4-oxide (chlordiazepoxide), 7-chloro-1-methyl-5-phenyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione (clobazam), 5-(2-chlorophenyl)-7-nitro-1H-1,4-Benzodiazepin-2(3H)-one (clonazepam), clonitazene, 7-chloro-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-3-carboxylic acid (chlorazepate), 5-(2-chlorophenyl)-7-ethyl-1-methyl-1H-thieno[2,3-e][1,4]diazepin-2(3H)-one (clotiazepam), 10-chloro-11b-(2-chlorophenyl)-2,3,7,11b-tetrahydrooxazolo[3,2-d][1,4]benzodiazepin-6(5H)-one (cloxazolam), (-)-methyl-[3β-benzoyloxy-2β(1αH,5αH)-tropane carboxylate (cocaine), 4,5α-epoxy-3-methoxy-17-methyl-7-morphinen-6α-ol (codeine), 5-(1-cyclohexenyl)-5-ethylbarbituric acid (cyclobarbital), cyclophosphane, cyclorphan, 7-chloro-5-(2-chlorophenyl)-1H-1,4-benzodiazepin-2(3H)-one (delorazepam), desomorphine, dextromoramide, (+)-(1-benzyl-3-dimethylamino-2-methyl-1-phenylpropyl) propionate (dextropoxyphene), desocine, diampromide, diamorphine, 7-chloro-1-methyl-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (diazepam), 4,5α-epoxy-3-methoxy-17-methyl-6α-morphinanol (dihydrocodeine), 4,5α-epoxy-17-methyl-3,6a-morphinandiol (dihydromorphine), dimenoxadol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol (dronabinol), eptazocine, 8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (estazolam), ethoheptazine, ethylmethylthiambutene, ethyl-[7-chloro-5-(2-fluorophenyl)-2,3-dihydro-2-oxo-1H-1,4-benzodiazepine-3-carboxylate] (ethyl loflazepate), 4,5α-Epoxy-3-ethoxy-17-methyl-7-morphinen-6α-ol (ethylmorphine), etonitazene, 4,5α-epoxy-7α-(1-hydroxy-1-methylbutyl)-6-methoxy-17-methyl-6,14-endo-etheno-morphinan-3-ol (etorphine), N-ethyl-3-phenyl-8,9,10-trinorbornan-2-ylamine (phencyclamine), 7-[2-(α-methylphenethylamino)-ethyl]theophylline (phenethyltheophylline), 3-(α-methylphenethylamino)propionitrile (fenproporex), N-(1-phenethyl-4-piperidyl)propionanilide (fentanyl), 7-chloro-5-(2-fluorophenyl)-1-methyl-1H-1,4-benzodiazepin-2(3H)-one (flurazepam), 5-(2-fluorophenyl)-1-methyl-7-nitro-1H-1,4-benzodiazepin-2-(3H)-one (flunitrazepam), 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2(3H)-one (flurazepam), 7-chloro-5-phenyl-1-(2,2,2-trifluoroethyl)-1H-1,4-benzodiazepin-2(3H)-one (halazepam), 10-bromo-11b-(2-fluorophenyl)-2,3,7,11b-tetrahydro[1,3]oxazolo[3,2-d][1,4]benzodiazepin-6(5H)-one (haloxazolam), heroin, 4,5α-epoxy-3-methoxy-17-methyl-6-morphinanone (hydrocodone), 4,5α-epoxy-3-hydroxy-17-methyl-6-morphinanone (hydromorphone), hydroxypethidine, isomethadone, hydroxymethylmorphinan, 11-chloro-8,12b-dihydro-2,8-dimethyl-12b-phenyl-4H-[1,3]oxazino[3,2-d][1,4]benzodiazepin-4,7(6H)-dione (ketazolam), 1-[4-(3-hydroxyphenyl)-1-methyl-4-piperidyl]-1-propanone (ketobemidone), (3S,6S)-6-dimethylamino-4,4-diphenylheptan-3-yl acetate (levacetylmethadol (LAAM)), (-)-6-dimethylamino-4,4-Diphenyl-3-heptanone (levomethadone), (-)-17-Methyl-3-morphinanol (levorphanol), levophenacylmorphan, lofentanil, 6-(2-Chlorophenyl)-2-(4-methyl-1-piperazinylmethylene)-8-nitro-2H-imidazo[1,2-a][1,4]benzodiazepin-1(4H)-one (loprazolam), 7-Chloro-5-(2-chlorophenyl)-3-hydroxy-1H-1,4-benzodiazepin-2(3H)-one (lorazepam), 7-Chloro-5-(2-chlorophenyl)-3-hydroxy-1-methyl-1H-1,4-benzodiazepin-2(3H)-one (lorametazepam), 5-(4-Chlorophenyl)-2,5-dihydro-3H-imidazo[2,1-a]isoindol-5-ol (mazindol), 7-Chloro-2,3-dihydro-1-methyl-5-phenyl-1H-1,4-benzodiazepine (medazepam), N-(3-Chloropropyl)-α-methylphenethylamine (mephenorex), meperidine, 2-Methyl-2-propyltrimethylenedicarbamate (meprobamate), meptazinol, metazosin, methylmorphine, N,α-Dimethylphenethylamine (methamphetamine), (±)-6-Dimethylamino-4,4-diphenyl-3-heptanone (methadone), 2-Methyl-3-o-tolyl-4(3H)-quinazolinone (metacalone), Methyl-[2-phenyl-2-(2-piperidyl)acetate] (methylphenidate), 5-Ethyl-1-methyl-5-phenylbarbituric acid (methylphenobarbital), 3,3-Diethyl-5-methyl-2,4-piperidinedione (methiprylon), methopon, 8-Chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo[1,5-a][1,4]benzodiazepine (midazolam), 2-(Benzohydrylsulfinyl)acetamide (modafinil), 4,5α-Epoxy-17-methyl-7-morphinen-3,6α-diol (morphine), mirofin, (±)-trans-3-(1,1-Dimethylheptyl)-7,8,10,10α-tetrahydro-1-hydroxy-6,6-dimethyl-6H-dibenz[b,d]Pyran-9(6αH)-one (nabilone), nalbuphine, nalorphine, narceine, nicomorphine, 1-methyl-7-nitro-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one ( nimetazepam), 7-nitro-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one ( nitrazepam), 7-chloro-5-phenyl-1H-1,4-benzodiazepin-2-(3H)-one ( nordazepam), norlevorphanol, 6-dimethylamino-4,4-diphenyl-3-hexanone ( normethadone), normorphine, norpipanone, the coagulated juice of plants belonging to the genus Papaver somniferum (opium), 7-chloro-3-hydroxy-5-phenyl-1H-1,4-benzodiazepin-2-(3H)-one ( oxazepam), (cis-trans)-10-chloro-2,3,7,11b-tetrahydro-2-methyl-11b-phenyloxazolo[3,2-d][1,4]benzodiazepin-6-(5H)-one ( oxazolam), 4,5α-epoxy-14-hydroxy-3-methoxy-17-methyl-6-morphinanone ( oxycodone), oxymorphone, plants belonging to the species Papaver somniferum (including the subspecies setigerum) (Papaver somniferum) and parts of such plants, papaveretum, 2-imino-5-phenyl-4-oxazolidinone ( pernolide), 1,2,3,4,5,6-hexahydro-6,11-dimethyl-3-(3-methyl-2-butenyl)-2,6-methano-3-benzazocin-8-ol ( pentazocine), 5-ethyl-5-(1-methylbutyl)barbituric acid ( pentobarbital), ethyl-(1-methyl-4-phenyl-4-piperidinecarboxylate) ( pethidine), phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, pholcodine, 3-methyl-2-phenylmorpholine ( phentermine), 5-ethyl-5-phenylbarbituric acid ( phenobarbital), α.α-dimethylphenethylamine ( phentermine), 7-chloro-5-phenyl-1-(2-propynyl)-1H-1,4-benzodiazepin-2(3)-one ( prazepam), α-(2-piperidyl)benzhydryl alcohol ( pipradrol), 1′-(3-cyano-3,3-Diphenylpropyl)[1,4′-bipiperidine]-4′-carboxamide (Piritramide), 7-chloro-1-(cyclopropylmethyl)-5-phenyl-1H-1,4-benzodiazepin-2(3H)-one (Prazepam), Profadol, Proheptazine, Promedol, Propiperidine, Propoxyphene, N-(1-methyl-2-piperidinoethyl)-N-(2-pyridyl)propionamide, methyl-{3-[4-methoxycarbonyl-4-(N-phenylpropanamide)piperidino]propanoate}(Remifentanil), 5, -sec-butyl-5-ethylbarbituric acid (Secobutabarbital), 5-allyl-5-(1-methylbutyl)barbituric acid (Secobarbital), N-{4-methoxymethyl-1-[2-(2-thienylethyl)-4-piperidyl}propionanilide (Sufentanil), 7-chloro-2-hydroxy-methyl-5-phenyl-1H-1,4-benzodiazepin-2-(3H)-one (Temazepam), 7-chloro-5-(1-cyclohexenyl)-1-methyl-1H-1,4-benzodiazepin-2(3H)-one (Tetrazepam), ethyl-(2-dimethylamino-1-phenyl-3-cyclohexane-1-carboxylate)(Tilidine (cis and trans)), Tramadol, 8-chloro-6-(2-chlorophenyl)-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (Triazolam), 5-(1-methylbutyl)-5-vinylbarbituric acid (Vinylbarbital), (1R*,2R*)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)phenol, (1R,2R,4S)-2-[(dimethylamino)methyl-4-(p-fluorobenzyloxy)-1-(m-methoxyphenyl)cyclohexanol are mentioned, each, optionally corresponding stereoisomeric compounds and corresponding derivatives, in particular, in the form of esters, or ethers, all physiologically compatible compounds, in particular salts and solvates are mentioned.

[0059] In some embodiments, the method utilizes one or more opioids such as hydrocodone, hydromorphone, morphine, oxycodone and / or their salts.

[0060] Non-limiting examples of APIs that can be used include inorganic synthetic drugs (such as aluminum hydroxide, magnesium trisilicate, etc.) or organic synthetic drugs (such as aspirin, chloramphenicol, caffeine, etc.). APIs also include antibiotics (for example, aminoglycosides, such as amikacin, gentamicin, kanamycin, etc.), ansamycins (such as geldanamycin, herbimycin, etc.), carbapenems (such as ertapenem, doripenem, cilastatin, etc.), cephalosporins (including first, second, third, fourth, and / or fifth generation cephalosporins such as cephradroxil, cefazolin, cefcapene, cefaclor, cefoxitin, cefosimile, cefixime, cefdinir, ceftriaxone, cefepime, cefaloram fosamil, cefobiprole, etc.).), glycopeptides (such as teicoplanin, vancomycin, etc.), lincosamides (such as clindamycin, etc.), lipopeptides (such as daptomycin, etc.), macrolides (such as azithromycin, clarithromycin, fidaxomicin, etc.), monobactams (such as aztreonam, etc.), nitrofurans (such as furazolidone, etc.), oxazolidinones (such as linezolid, etc.), penicillins (such as amoxicillin, etc.), polypeptides (such as bacitracin, colistin, polymyxin B, etc.), quinolone / fluoroquinolone (such as ciprofloxacin, enoxacin, levofloxacin, etc.), sulfonamides (such as mafenide, sulfacetamide, etc.), tetracyclines (such as demeclocycline, doxycycline, etc.). APIs also include plant estrogens such as genistein and daidzein, various phytochemicals such as isoflavones (such as soy isoflavones), flavonoids, phytoalexins (such as resveratrol (3,5,4’-trihydroxystilbene)), red clover extract, phytosterols, or compounds containing phytochemicals may also be mentioned.

[0061] Other active chemical substances may include, for example, essential fatty acids containing polyunsaturated fatty acids such as omega-3 fatty acids, omega-6 fatty acids, omega-9 fatty acids, conjugated fatty acids, etc., fat-soluble vitamins including vitamin D3 and vitamin A palmitate; alpha lipoic acid, other oils, coenzymes including coenzyme Q10, carotenoids including lycopene, lutein, zeaxanthin, etc.

[0062] Other active chemical substances may include therapeutic compounds contained in various therapeutic oils or plant extracts, including but not limited to cannabinoids such as cannabidiol. In some embodiments, cannabis oil is utilized.

[0063] Other active chemical substances may include inorganic materials including graphene or graphene oxide, and metal oxides such as aluminum oxide, calcium oxide, chromium oxide, cobalt oxide, iron oxide, lead oxide, lithium oxide, silicon dioxide, titanium dioxide, and / or zinc oxide.

[0064] Other active chemical substances may include industrially useful organic substances including alkanes and unsaturated hydrocarbons.

[0065] Other active chemical substances may include, for example, foods or food additives including NaCl.

[0066] In addition to active chemical substances, appropriate biological substances may also be utilized. For example, in some embodiments, the biological material is a biomolecule. That is, typically, it is a compound composed of one or more chemical moieties synthesized in vivo. Non-limiting examples of biomolecules include amino acids, nucleotides, polysaccharides or monosaccharides, lipids, or combinations thereof.

[0067] In some embodiments, in contrast to purified biomolecules (e.g., purified enzymes), biological materials include cells and / or cell debris. In some embodiments, biological materials can be viruses (e.g., bacteriophages), cells (e.g., microorganisms), tissues, and organisms (e.g., plants), or can be obtained from them using conventional known techniques.

[0068] Solvent Liquids generally contain at least one solvent. Preferred embodiments utilize water as the solvent, but other solvents can also be included. In some embodiments, the solvent is a pharmaceutically acceptable solvent. Non-limiting examples of pharmaceutically acceptable solvents include ketones such as acetone, alcohols such as methanol, ethanol, and propanol, mixtures thereof, and mixed solvents of water and one or more of these solvents. These pharmaceutically acceptable solvents can be used alone or in appropriate combinations of two or more.

[0069] In some embodiments, the liquid is non-aqueous. In some embodiments, the solvent is an oil suitable for human consumption, such as castor oil, soybean oil, sunflower oil, coconut oil, sesame oil, or olive oil. In some embodiments, the solvent comprises, consists of, or consists essentially of one or more saturated fatty acids, one or more unsaturated fatty acids, or combinations thereof.

[0070] The concentration of the active chemical or biological substance present in the liquid is not particularly limited. Preferably, the active chemical or biological substance can be dispersed in the liquid. In some embodiments, the concentration of the active chemical or biological substance is 0.01 wt% to 99 wt% of the liquid. In some embodiments, the concentration of the active chemical or biological substance is 0.01 wt% to 50 wt% of the liquid. In some embodiments, the concentration of the active chemical or biological substance is 0.1 wt% to 30 wt% of the liquid. In some embodiments, the concentration of the active chemical or biological substance is 1 wt% to 20 wt% of the liquid.

[0071] The device may include one or more connectors 160. Each connector may be operably coupled to a first end 111 of the first tubular member 110, a second end 112 of the first tubular member 110, or one of the first ends 121 of at least one second tubular member 120.

[0072] Connectors generally enable the device to be operably coupled to one or more fluid sources, and thus, the connectors may include any suitable connection to the tubular member, i.e., threads, ridges, adhesives, welding, etc. In some embodiments, the connectors are removably coupled to the device. In some embodiments, the connectors are permanently fixed to the device.

[0073] As seen in FIG. 1, the device may include a single second lumen 114 and a single second tubular member 120. Referring to FIG. 4, the device may include a plurality of second lumens 114 and a plurality of second tubular members 120, each of which is directed toward one of the plurality of second lumens 114. Preferably, the number of second lumens 114 is equal to the number of second tubular members 120.

[0074] In some embodiments, the plurality of second lumens 114 may be linearly arranged, spaced apart by an axial distance. In some embodiments, the plurality of second lumens 114 may be spaced apart by an axial distance and a circumferential distance. For example, if the first lumen 113 extends from left to right, the second lumen 114 may be oriented directly below (e.g., in the vertical direction), while an adjacent second lumen 114 may be separated by a few centimeters to the left or right and oriented at an angle, e.g., up to 30 degrees, 60 degrees, 90 degrees, or 180 degrees from the vertical downward direction.

[0075] Referring to FIG. 5, the device may include at least one third tubular member 510 that may have an inner diameter 518 that is larger than the outer diameter 519 of the first tubular member 110. The first tubular member 110 and the at least one third tubular member 510 may be concentrically arranged (e.g., around the central axis 520 of the first tubular member 110) and may be configured to produce core-shell particles 150 having a plurality of shells 152, 153 around a core 151. The outer shell(s) are from the fluid flowing through the third tubular member(s) 510.

[0076] The at least one third tubular member 510 may have at least one third inner lumen 514 that is positioned such that particles exiting the at least one second inner lumen 114 also pass through the at least one third inner lumen 514. The second inner lumen 114 and the third inner lumen 514 may be coaxial (e.g., the central axes 521 of the second inner lumen 114 and the third inner lumen 514 may be the same).

[0077] In these arrangements, the innermost layer of the shell around the core is formed from the fluid flowing through the first tubular member 110, and the outermost layer(s) of the shell are formed from the fluid flowing through the third tubular member(s) 510.

[0078] Referring to FIG. 6, the device may include at least one fourth tubular member 620 having an inner diameter 621 that is larger than the outer diameter 622 of at least one second tubular member 120. The at least one second tubular member 120 and the at least one fourth tubular member 620 may be concentrically arranged (e.g., around a central axis 623). The tubular members may be configured to produce a core that includes a plurality of materials 651, 652. For ease of illustration, the particles 150 in FIG. 6 are shown as having a core where the left half is one material and the right half is a second material. However, it is understood that any arrangement of materials can be produced depending on operating conditions, fluid selection, etc. In some embodiments, the materials forming the core are uniformly distributed. In some embodiments, the materials forming the core are non-uniformly distributed. In some embodiments, the materials forming the core are arranged in layers.

[0079] As will be appreciated, these configurations can be used in combination. For example, in one embodiment, the device includes a single first tubular member 110, a single second tubular member 120, a single third tubular member 510, and a single fourth tubular member 620. In some embodiments, the single second tubular member and the fourth tubular member 620 may form an injection device, and there may be more than two injection devices introduced into the same first tubular member 110 (or the first tubular member 110 and the third tubular member(s) 510).

[0080] In various aspects, a system can be provided. Referring to FIG. 7, system 700 can include device 100 for generating substantially uniform core-shell particles as disclosed herein. The system can include a first fluid source 710 operably coupled to a first end 111 of a first tubular member 110, and the first fluid source 710 is configured to provide a first fluid 130. The system can include a pump 712, or other means, for supplying and controlling the flow of fluid through the first tubular member 110. As understood, the pump 712 can additionally or alternatively supply the first fluid 130 to a second end. Optionally, an additional pump 713 and / or fluid source 711 can be used to provide the first fluid 130 to the second end as desired.

[0081] The system can include a second fluid source 720 operably coupled to a first end 121 of at least one second tubular member 120, and the second fluid source 720 is configured to supply a second fluid 140.

[0082] The first fluid 130 can include a liquid. The first fluid 130 can include, for example, one or more UV curable resins. The first fluid 130 can include one or more volatile solvents. The first fluid 130 can include one or more solids such as microparticles. The first fluid 130 can include a colorant such as a pigment or a dye, for example.

[0083] The second fluid 140 can include a liquid. The second fluid 140 can include a gas. The second fluid 140 can include microparticles. The second fluid 140 can include one or more amino acids. The second fluid 140 can include one or more pharmaceutical active ingredients. In some embodiments, the first fluid 130 and the second fluid 140 do not include a surfactant.

[0084] The system can include a container 730 for collecting core-shell particles 150 that move along a path extending away from the second lumen 114.

[0085] The system may collectively include at least one controller 740 that controls the flow of fluid through the device such that core-shell particles are formed and directed from at least one second lumen 114. The controller may be connected to one or more components, such as pumps 712, 722, for example.

[0086] The term "controller" is intended to include any analog or digital means for controlling a process and may include one or more circuits and / or one or more processors.

[0087] The term "processor" as used herein includes, but is not limited to, at least one integrated circuit, or any other electronic device (or collection of electronic devices) that can perform operations on at least one instruction, including a microprocessor (μP), a microcontroller (μC), a digital signal processor (DSP), or any combination thereof. The processor may further be a RISC (Reduced Instruction Set Core) processor, a CISC (Complex Instruction Set Computing) microprocessor, an MCU (Microcontroller Unit), or a CISC-based CPU (Central Processing Unit). The hardware of the processor may be integrated on a single substrate (e.g., a silicon "die") or distributed across two or more substrates. Further, various functional aspects of the processor may be implemented as software (or firmware) associated with the processor only. The term "circuit" may refer to one or more passive components and / or active components arranged to cooperate with each other to provide a desired function.

[0088] The system may include a drying means 750 (e.g., an air dryer, a freeze dryer, a drum dryer, a tray dryer, etc.), a photopolymerization means 751 (e.g., a UV, visible light, or IR light source, etc. adapted to activate a photopolymer present in one of the fluids), or a thermal decomposition means 752 (e.g., a thermal decomposition reactor, etc.), which is operatively coupled to / regulated by a controller. The drying, photopolymerization, or thermal decomposition means may be configured to convert at least one layer of the core-shell particles formed by the device from a liquid to a solid.

[0089] The core-shell particles may be converted into an aerosol (or as an aerosol). The core-shell particles may be converted on a surface (e.g., the surface 731 of the container 730, etc.).

[0090] In various aspects, a kit may be provided. The kit may include a device for generating substantially uniform core-shell particles as disclosed herein. The kit may include a drying means and / or a photopolymerization means.

[0091] In various aspects, a method for generating substantially uniform layered core-shell particles may be provided. Referring to FIG. 8, the method 800 may include supplying 810 a first fluid 130 to a first inner cavity 113 of a device for generating substantially uniform core-shell particles as disclosed herein.

[0092] In various embodiments, the pressure of the first fluid 130 may be a gauge pressure of 5 kPa to 1000 kPa.

[0093] The pressure of the first fluid 130 may open a second inner cavity 114 and form a fluid film that spreads into the opened second inner cavity 114.

[0094] The method may include generating substantially uniform core-shell particles (820). This may include supplying a second fluid 140 to a second tubular member 120 (821). The second tubular member 120 may be configured to direct the second fluid 140 through a fluid film, such that core-shell particles are formed having a shell of a first fluid 130 surrounding a core containing the second fluid 140. The first fluid 130 and the second fluid 140 may not include a surfactant.

[0095] In various embodiments, the pressure of the second fluid 140 may be a gauge pressure between 5 kPa and 2000 kPa.

[0096] Generating the particles may include passing at least one additional core fluid through at least one additional tubular member disposed concentrically around the second tubular member 120 (822) to form a single-shell sphere having a multi-material core of gas, liquid, or a combination thereof. The additional core fluid may be supplied at the same pressure as the second fluid 140. The additional core fluid may be supplied at a pressure different from the second fluid 140. In various embodiments, the pressure of the additional core fluid may be between a gauge pressure of 5 kPa and 2000 kPa.

[0097] Generating the particles may include passing the core-shell particles through one additional fluid stream (a "shell fluid") passing through at least one tubular member disposed concentrically around the first tubular member 110 (823) to form a multi-shell sphere around a core of gas or liquid. The additional shell fluid may be supplied at the same pressure as the first fluid 130. The additional shell fluid may be supplied at a pressure different from the first fluid 130. In various embodiments, the pressure of the additional shell fluid may be between a gauge pressure of 5 kPa and 1000 kPa.

[0098] The method may include modifying the output from the device in some way 830. The method may include drying (831), or at least partially drying, the core-shell particles (e.g., by exposing the particles to hot, dry air). The method may include photopolymerizing (832) the shell, and / or the core, of the core-shell particles (e.g., by exposing particles containing a photopolymer to a UV light source). The method may include pyrolyzing (833) the core-shell particles (e.g., in a pyrolyzer). The method may include causing a chemical reaction (834) in at least one layer of the core-shell particles.

[0099] The method may include collecting (840) the core-shell particles. This includes collecting them in a container (e.g., a bottle), or a dish.

[0100] The method may include foaming (850) the core-shell particles. This may occur naturally when the particles are collected. However, foaming can be prevented by including an anti-foaming agent, or a defoaming agent.

[0101] In various embodiments, each core-shell particle may include, hereinafter, any of (i) a microsphere having a single layer fluid shell and a single material fluid core, (ii) a microsphere having a multi-layer fluid shell and a single material fluid core, (iii) a microsphere having a single layer fluid shell and a multi-material fluid core, or (iv) a microsphere having a multi-layer fluid shell and a multi-material fluid core.

[0102] The fluid shell may include a liquid. The fluid shell may include a solid. The fluid core may include a gas. The fluid core may include a liquid. The fluid core may include a solid.

[0103] In a set of examples, the first fluid 130 was either (i) water, (ii) glycerol, or water mixed with polysorbate 80, and the second fluid 140 was air.

[0104] This method may include controlling the generation of particles (860). This may include adjusting 861 the pressure of the first fluid 130 to control the outlet area of the second lumen 114. When the first tubular member 110 is flexible / elastic, increasing the pressure can increase the size of the outlet area.

[0105] This may include adjusting (862) the pressure, density, surface tension, and viscosity of the first fluid 130 to control the size and shell thickness of the core-shell particles. This may alternatively or additionally include adjusting those parameters of the third fluid. The physical properties of the fluid may be adjusted by a temperature regime (heating or cooling the fluid) or by selecting a fluid having appropriate properties at room temperature. For example, as the pressure of such a fluid increases relative to the pressure of the second fluid 140, the thickness of the shell formed by that fluid decreases.

[0106] This may include adjusting 863 the pressure of the second fluid 140 to control the size of the core-shell particles. This may alternatively or additionally include adjusting the pressure of the fourth fluid. For example, when the pressure of such a fluid increases relative to the pressure of the first fluid 130, the volume of the core increases and the flow rate of the core-shell generating particles also increases.

[0107] In some embodiments, the pressure of the second tubular member 120, the first lumen 113, and the first fluid 130 may be configured to provide core-shell particles having an outer diameter of about 200 microns or less. The required size of the generated core-shell particles can be manipulated by combining the surface tension of the first liquid 130 and, independently or via the pressure of the first liquid 130, the size of the first lumen 113, the size of the second lumen 114, and the pressure of the second liquid.

[0108] In some embodiments, core-shell particles of at least 10 mL / min can pass through a single second lumen 114, which can be achieved by selecting an appropriate combination of the pressure within the second tubular member 120 and the surface tension, density, and viscosity of the first fluid 130.

[0109] The disclosed approach can be used as a process technology for manufacturing products, for example, for manufacturing aerosols having liquid or solidified core-shell particles, which can carry, for example, a medicament that can be directed to the human airway (e.g., nasal drug delivery).

[0110] A simplified example can be seen in FIG. 9. There, a drug delivery device 900 is shown having a first housing 910 with a port 912 for dispensing the formed aerosol. The device 100 disclosed herein is configured to direct particles towards the first port. The device is operably coupled to a source of gas (here, the source is ambient air through an air inlet 914) and a source of fluid for delivery to a user (here, shown as a first fluid source 710), for example, via one or more pumps 712, 722. In some embodiments, a second housing 920 may be removably coupled to the first housing (e.g., via threads, interacting extrusions, and depressions, tabs, etc.). The second housing may include a source of fluid containing an active pharmaceutical ingredient (API) or other substance for delivery to the user. In some embodiments, the second housing may include a film 922, such as a metallized film, configured to be penetrated by a needle 916 operably coupled to the device 100, such that when the second housing is coupled to the first housing, the film is penetrated and the material within the second housing can flow into the device 100. The device may include other components necessary for using the delivery device, such as a battery coupled to a controller 740. The device may include, for example, a button 940 for activating the device, and may include one or more other indicators 950 or displays, or a port 960 (such as a charging port or an I / O communication port, etc.).

[0111] In various aspects, alternative systems may be provided that are configured to generate particles containing micron-sized droplets, sub-micron-sized droplets, or microencapsulated substances.

[0112] Referring to FIG. 10, system 1000 may include an atomization device 1001. The chamber may be disposed within a chemical fume hood 1050 having an exhaust port 1060. A liquid 1003 formed by including a plurality of immiscible liquid layers is within an atomization chamber 1002 in the atomization device. A gas source 1005 is supplied through a tube 1006 to a tube 1010 within the atomization chamber. The gas supply may optionally be controlled by a regulator 1007 and may optionally include a pressure gauge 1008 downstream of the regulator. The tube 1010 may be configured to be partially immersed in the liquid. The tube may include openings penetrating the sidewall of the tube, and the openings are arranged such that at least some of the openings are configured to direct a gas jet toward bubbles on the surface of the liquid to form particles containing micron-sized droplets, sub-micron-sized droplets, or microencapsulated substances.

[0113] The liquid may include a plurality of immiscible liquid layers.

[0114] The plurality of immiscible liquid layers may include a first layer containing a first material R, a second layer containing a second material G, and a third material B in the first layer and / or the second layer, and R, G, and B are selected such that γRB > γRG + γGB, where γRB is the interfacial surface tension between materials R and B, γRG is the interfacial surface tension between materials R and G, and γGB is the interfacial surface tension between materials G and B.

[0115] Compressed air generates an aerosol of droplets suspended in air 1015.

[0116] Thereafter, the aerosol can be transported, for example, through a hose 1025 (e.g., a "guide tube"), towards a collection chamber 1040 equipped with a HEPA filter 1045. Accordingly, the system can include a guide tube coupled to the top of the atomization chamber. The guide tube can be UV-transparent. The guide tube can be configured to have a heated wall, an insulated wall, or a cooled wall. The guide tube can include a bottom coupled to the atomization chamber. The bottom, and / or sidewalls, of the guide tube can be configured to have openings for entraining external ambient gas for mixing with the aerosol within the guide tube.

[0117] The system can include an ultraviolet (UV) light source 1026 configured to irradiate the aerosol within the guide tube. The system can include electrical heating 1027, or a cooling coil, coupled to the guide tube.

[0118] The system can include a parabolic mirror configured to collect solar energy for irradiating the guide tube.

[0119] The system can include a pyrolyzer coupled to the guide tube. In some embodiments, the system can include a burner coupled to the end of the guide tube, and the burner is configured to solidify, dehydrate, or pyrolyze the aerosol droplets.

[0120] The system can include at least one chamber configured to form a dry particle aerosol through solvent evaporation of the submicron droplet aerosol. The system can include a particle collector configured to collect dry particles from the dry particle aerosol. The system can include a liquid, solid, or electrostatic filter for capturing particulate matter from the aerosol stream flowing through the guide tube.

[0121] Within the collection chamber, the aerosol stream can be directed towards a coolant droplet trap that includes an aluminum cylindrical container 1030 having a filter 1031. In some embodiments, the container can be at least partially surrounded by a molten water ice bath 1032. The aerosol passing through the cooled droplet trap is cooled, its entropy is decreased, the surface area of the aerosol is decreased, and the droplets coalesce to form larger droplets. The heavier droplets precipitate onto the walls of the droplet trap and merge by gravity to form a liquid volume 1033 at the bottom of the trap.

[0122] Particles containing micron-sized droplets, sub-micron-sized droplets, or microencapsulated materials can include a single-layer shell. Droplets or particles having a single-layer shell can include a single-material core. Droplets or particles having a single-layer shell can include a multi-material core. Micron-sized droplets, sub-micron-sized droplets, or particles containing microencapsulated materials include a multi-layer shell. Droplets or particles having a multi-layer shell can include a single-material core. Droplets or particles having a multi-layer shell can include a multi-material core. In some embodiments, all of the shells can be liquid or solid, or one or more of the shells can be liquid and one or more of the shells can be solid. In some embodiments, the core can be liquid or solid, or the core can include a mixture of solid material and liquid material.

[0123] Figures 11A - 11B show various approaches available within the atomization chamber.

[0124] In FIG. 11A, one technique 1100 is generally shown as involving supplying a liquid 1110 to a container 1120. In a preferred embodiment, the container is or forms part of an atomization chamber. The container is preferably composed of glass, stainless steel, and / or any non-reactive material suitable for containing the particular liquid used. The container is generally at least partially sealed. The container 1120 may have one or more inlets, or ports 1112, 1113, 1114. One inlet 1112 may be configured to pump the liquid into the container. As will be understood by those skilled in the art, the container may include a sensor (not shown) configured to detect the level of the liquid within the container, and if the sensor determines that there is no threshold level of the liquid, a processor (not shown) may be utilized to pump the liquid into the container. One inlet 1113 may be configured to pump air into the container to generate bubbles. As will be understood by those skilled in the art, this inlet may be operably connected, via at least one valve, or regulator (not shown), to, for example, a compressed gas storage tank (not shown). And one inlet 1114 may be configured to connect to a perforated tube, or pipe 1115, which is configured to have a plurality of holes 1116 that penetrate the tube, or pipe wall, in order to direct the gas towards the bubbles at or near the surface of the liquid. Preferably, the perforated tube, or pipe 1115 is arranged to be partially immersed, with at least some of the holes 1116 above the liquid surface and at least some of the holes at or below the liquid surface. In some embodiments, the tube extends across the atomization chamber. In some embodiments, the tube is configured to be connectable to a plurality of pressurized gases, such that a mixed gas can enter the atomization chamber through the tube. In some embodiments, the inlet 1113 is operably connected to a one-way valve (e.g., via a quick disconnect fitting) configured such that the connection to the gas supply is removably attached.In some embodiments, each end of the tube is operably connected to a one-way valve, and each one-way valve is configured to be removably connected to one or more gas supplies (such as one or more compressed gas tanks, etc.).

[0125] In a preferred embodiment, the aeration diffuser disk, or ring 1117, is not utilized. Instead, an arrangement as shown in FIG. 11B is utilized. In a preferred embodiment 1150, a tube 1160, more preferably a flexible tube, having openings (such as ports, nozzles, perforations, or holes) 1161, 1162 that penetrate the sidewall of the tube is provided. The tube 1160 is disposed within the atomization chamber such that at least some of the openings 1161 are located above the gas-liquid interface (sometimes simply referred to as the "surface") 1156 of the multi-layer liquid 1155, and at least some of the openings 1162 are located below the surface 1156. When gas is supplied to the inlet of the tube 1160, bubbles 1170 are first formed in the bulk liquid from the gas exiting the sub-surface openings 1162 and initially have only a single shell layer, but as the bubbles pass through each layer 1152, 1153, additional layers are added to the outer shell. When the gas exits through the openings 1161 on the surface, they interact to break up the multi-layer bubbles 1175 and form multi-layer particles 1180.

[0126] Accordingly, in various aspects, a method of generating particles containing micron-sized droplets, sub-micron-sized droplets, or micro-encapsulated substances may be provided. Referring to FIG. 12, the method 1200 may include providing (1210) a liquid including a plurality of immiscible liquid layers.

[0127] The layers may include one or more aqueous layers. The layers may include one or more anhydrous layers. The layers may include a silicone layer.

[0128] The method may include aerating a liquid (1220) in an atomization chamber to form bubbles that pass through each of a plurality of immiscible liquid layers such that the bubbles rise to the surface of the liquid. The method may include forming a submicron droplet aerosol (1230) by ejecting a gas jet through an opening in a tube toward at least one of the bubbles in the atomization chamber.

[0129] The method may include adjusting the temperature in a guide tube (1240) coupled to the upper portion of the atomization chamber. This may include heating the aerosol in the tube (1241). This may include cooling the aerosol in the tube (1242).

[0130] The method may include entraining an external ambient gas (1250) through an opening in a portion of the guide tube for mixing with the aerosol in the guide tube, the opening being coupled to a sidewall of the atomization chamber and / or the guide tube.

[0131] The method may include photopolymerizing a material within a droplet or particle (1260) by irradiating ultraviolet (UV) light toward the aerosol in the guide tube.

[0132] The method may include solidifying, dehydrating, and / or pyrolyzing the aerosol droplets (1270).

[0133] The method may include forming a dry particle aerosol (1280) via solvent evaporation of the submicron droplet aerosol.

[0134] The method may include forming a powder of submicron or nanostructured particles (1290) by passing the dry particle aerosol through a particle collector.

Claims

**Claim 1** A device for generating substantially uniform core-shell particles, comprising: a first tubular member 110 having a first end and a second end, said first tubular member 110 having a first lumen 113 and at least one second lumen 114, said first lumen 113 extending from said first end to said second end, each said second lumen 114 extending from an outer surface of said first tubular member 110 through a sidewall of said first tubular member 110 and connecting to said first lumen 113 at a position axially spaced from said first end; a first tubular member 110; at least one second tubular member 120 having a first end positioned outside said first tubular member 110 and a second end within said first lumen 113 and directed toward one of said at least one second lumens 114, said at least one second tubular member 120 extending through a sidewall of said first tubular member 110; and a second tubular member. **Claim 2** The device of claim 1, further comprising at least one connector, each connector being operably coupled to one of said first end of said first tubular member 110, said second end of said first tubular member 110, or said first end of said at least one second tubular member 120. **Claim 3** The device of claim 2, wherein said first tubular member 110 comprises an elastic material. **Claim 4** The device of claim 3, wherein when pressurized liquid is supplied to said first lumen 113, said at least one second lumen 114 opens or expands. **Claim 5** The device of claim 4, wherein said at least one second tubular member 120 comprises a rigid material. **Claim 6** The device of claim 5, wherein said at least one second tubular member 120 has an inner diameter D with 10 μm < D < 1 mm and a wall thickness T with 10 μm < T < 1 mm. **Claim 7** The device of claim 1, wherein said device comprises a single second lumen 114 and a single second tubular member 120. **Claim 8** The device of claim 1, wherein said device comprises a plurality of second lumens 114 and a plurality of second tubular members 120, each directed toward one of said plurality of second lumens 114. **Claim 9** The device according to claim 1, further comprising at least one third tubular member 510 having an inner diameter larger than the outer diameter of the first tubular member 110, wherein the first tubular member 110 and the at least one third tubular member 510 are concentrically arranged and configured to generate core-shell particles having a plurality of shells around a core.

10. The device according to claim 9, having at least one third inner cavity 514, wherein the at least one third tubular member 510 is arranged such that particles exiting the at least one second inner cavity 114 also pass through the at least one third inner cavity 514.

11. The device according to claim 1 or 9, further comprising at least one fourth tubular member 620 having an inner diameter larger than the outer diameter of the at least one second tubular member 120, wherein the at least one second tubular member 120 and the at least one fourth tubular member 620 are concentrically arranged and configured to generate a core containing a plurality of materials.

12. A system comprising: the device according to claim 1; a first fluid source 710 operably coupled to the first end of the first tubular member 110, the first fluid source 710 being configured to provide a first fluid 130; a second fluid source 720 operably coupled to the first end of the at least one second tubular member 120, the second fluid source 720 being configured to provide a second fluid 140.

13. The system according to claim 12, wherein the first fluid 130 is a liquid and the second fluid is a gas.

14. The system according to claim 12, wherein the first fluid 130 is a first liquid and the second fluid 140 is a second liquid different from the first liquid.

15. The system according to claim 12, wherein the first fluid 130 and the second fluid 140 do not contain a surfactant.

16. The system according to claim 12, further comprising a container for collecting core-shell particles that move along a path extending in a direction away from the at least one second inner cavity 114.

17. The system of claim 12, further comprising at least one controller configured to control the flow of fluid through the device, enabling the formation of core-shell particles and being directed from at least one second lumen 114.

18. The system of claim 17, further comprising drying means, photopolymerization means, or pyrolysis means coupled to the at least one controller and configured to convert at least one layer of the core-shell particles formed by the device from a liquid to a solid.

19. The system of claim 17, wherein the core-shell particles are converted in an aerosol.

20. The system of claim 17, wherein the core-shell particles are converted on a surface.

21. A kit comprising: at least one device according to claim 1; and drying means and / or photopolymerization means.

22. A method for generating substantially uniform layered core-shell particles, comprising: supplying a first fluid 130 to the first lumen 113 of the device of claim 1, opening the second lumen 114 by the pressure of the first fluid 130, and forming a fluid film that spreads into the opened second lumen 114; and generating substantially uniform core-shell particles by supplying a second fluid 140 to the second tubular member 120 configured to direct the second fluid 140 through the fluid film, thereby forming core-shell particles having a shell comprising the first fluid 130 surrounding a core comprising the second fluid 140.

23. The method of claim 22, further comprising drying the core-shell particles.

24. The method of claim 22, further comprising photopolymerizing the shell and / or the core of the core-shell particles.

25. The method of claim 22, further comprising pyrolyzing the core-shell particles.

26. The method of claim 22, further comprising causing a chemical reaction in at least one layer of the core-shell particles.

27. The method of claim 22, further comprising collecting the core-shell particles.

28. The method according to claim 22, further comprising passing the core-shell particles through at least one tubular member concentrically disposed around the first tubular member 110 in one additional fluid stream to produce a multi-shell sphere around a gas or liquid core.

29. The method according to claim 22, further comprising passing at least one additional fluid through at least one additional tubular member concentrically disposed around the second tubular member 120 to form a single-shell sphere having a core of a plurality of materials of gas, liquid, or a combination thereof.

30. The method according to claim 22, wherein the first fluid 130 and the second fluid 140 do not contain a surfactant.

31. The method according to claim 22, wherein each core-shell particle comprises one of the following: A microsphere having a single-layer fluid shell and a single-material fluid core, A microsphere having a multi-layer fluid shell and a single-material fluid core, A microsphere having a single-layer fluid shell and a multi-material fluid core, or A microsphere having a multi-layer fluid shell and a multi-material fluid core.

32. The method according to claim 31, wherein the fluid shell contains a liquid.

33. The method according to claim 31, wherein the fluid shell contains a solid.

34. The method according to claim 31, wherein the fluid core contains a gas.

35. The method according to claim 31, wherein the fluid core contains a liquid.

36. The method according to claim 31, wherein the fluid core contains a solid.

37. The method according to claim 22, wherein the pressure of the first fluid 130 is adjusted to control the exit area of the second inner cavity 114.

38. The method according to claim 22, wherein the pressure of the first fluid 130 is adjusted to control the size of the core-shell particles.

39. The method according to claim 38, wherein the pressure of the second tubular member 120, the first inner cavity 113, and the first fluid 130 are configured to provide core-shell particles having an outer diameter of about 200 microns or less.

40. The method according to claim 22, wherein at least 10 mL / min of the core-shell particles pass through a single second inner cavity 114.

41. The method according to claim 22, further comprising causing the core-shell particles to foam.

42. A system for generating particles containing micron-sized droplets, sub-micron-sized droplets, or microencapsulated substances, wherein the system comprises: an atomization chamber; a tube within the atomization chamber, the tube being configured to be partially immersed in a liquid, the tube including an opening penetrating through a sidewall of the tube, the opening being arranged such that at least some of the openings are configured to direct a gas jet towards a bubble on the surface of the liquid for forming particles containing micron-sized droplets, sub-micron-sized droplets, or microencapsulated substances; the system wherein the liquid consists of a plurality of immiscible liquid layers. **Claim 43** The system according to claim 42, wherein the plurality of immiscible liquid layers include a first layer containing a first material R, a second layer containing a second material G, and a third material B in the first layer and / or the second layer, and R, G, and B are selected such that γRB > γRG + γGB, where γRB is the interfacial surface tension between materials R and B, γRG is the interfacial surface tension between materials R and G, and γGB is the interfacial surface tension between materials G and B. **Claim 44** The system according to claim 42, wherein the particles containing micron-sized droplets, sub-micron-sized droplets, or microencapsulated substances include a single-layer shell. **Claim 45** The system according to claim 44, wherein the particles containing micron-sized droplets, sub-micron-sized droplets, or microencapsulated substances include a single-material core. **Claim 46** The system according to claim 44, wherein the particles containing micron-sized droplets, sub-micron-sized droplets, or microencapsulated substances include a multi-material core. **Claim 47** The system according to claim 42, wherein the particles containing micron-sized droplets, sub-micron-sized droplets, or microencapsulated substances include a multi-layer shell. **Claim 48** The system according to claim 47, wherein the particles containing micron-sized droplets, sub-micron-sized droplets, or microencapsulated substances include a single-material core. **Claim 49** The system according to claim 47, wherein the particles containing micron-sized droplets, sub-micron-sized droplets, or microencapsulated substances include a multi-material core. **Claim 50** The system of claim 49, wherein all of the shells are liquid, all of the shells are solid, or one or more of the shells are liquid and one or more of the shells are solid.

51. The system of claim 50, wherein the core is liquid, the core is solid, or the core is a mixture of solid and liquid.

52. The system of claim 42, further comprising a guide tube coupled to an upper portion of the atomization chamber.

53. The system of claim 52, wherein the guide tube is ultraviolet (UV) transmissive.

54. The system of claim 52, wherein the guide tube is configured to have a heated, insulated, or cooled wall.

55. The system of claim 52, wherein the guide tube includes a bottom coupled to the atomization chamber, and the bottom and / or side walls of the guide tube are configured to have openings for entraining an external ambient gas for mixing with the aerosol within the guide tube.

56. An ultraviolet (UV) light source configured to irradiate the aerosol within the guide tube; An electrical heating or cooling coil coupled to the guide tube; A parabolic mirror configured to collect solar energy for irradiating the guide tube; A burner coupled to an end of the guide tube, the burner being configured to solidify, dehydrate, or pyrolyze aerosol droplets; At least one chamber configured to form a dry particle aerosol via evaporation of a solvent of a submicron droplet aerosol; A particle collector configured to collect dry particles from the dry particle aerosol; and / or A liquid, solid, or electrostatic filter configured to capture particulate matter from the aerosol flow flowing through the guide tube, the system of claim 52.

57. A method for generating particles containing micron-sized droplets, submicron-sized droplets, or microencapsulated materials, the method comprising: Providing a liquid containing a plurality of immiscible liquid layers; Ventilating the liquid within an atomization chamber to form bubbles passing through each of the plurality of immiscible liquid layers such that the bubbles rise to the surface of the liquid; and Forming a submicron droplet aerosol by directing a gas jet through an opening of a tube toward at least one of the bubbles within the atomization chamber.

58. A plurality of immiscible liquid layers include a first layer containing a first material R, a second layer containing a second material G, and a third material B in the first layer and / or the second layer, where R, G, and B are selected such that γRB > γRG + γGB, where γRB is the interfacial surface tension between materials R and B, γRG is the interfacial surface tension between materials R and G, and γGB is the interfacial surface tension between materials G and B. The method according to claim 57.

59. The method according to claim 57, wherein the particles containing the micron-sized droplets, sub-micron-sized droplets, or microencapsulated substances include a single-layer shell.

60. The method according to claim 59, wherein the particles containing the micron-sized droplets, sub-micron-sized droplets, or microencapsulated substances include a single-material core.

61. The method according to claim 59, wherein the particles containing the micron-sized droplets, sub-micron-sized droplets, or microencapsulated substances include a multi-material core.

62. The method according to claim 57, wherein the particles containing the micron-sized droplets, sub-micron-sized droplets, or microencapsulated substances include a multi-layer shell.

63. The method according to claim 62, wherein the particles containing the micron-sized droplets, sub-micron-sized droplets, or microencapsulated substances include a single-material core.

64. The method according to claim 62, wherein the particles containing the micron-sized droplets, sub-micron-sized droplets, or microencapsulated substances include a multi-material core.

65. The method according to claim 64, wherein all the shells are liquid, all the shells are solid, or one or more shells are liquid and one or more shells are solid.

66. The method according to claim 65, wherein the core is liquid, the core is solid, or the core is a mixture of solid and liquid.

67. Heating or cooling a guide tube coupled to the upper part of the atomization chamber. Entraining external ambient gas through an opening of a portion of the guide tube coupled to the side wall of the atomization chamber and / or the guide tube and mixing it with the aerosol in the guide tube. Photopolymerizing the material in the bubbles by irradiating the aerosol in the guide tube with ultraviolet (UV) light. Solidifying, dehydrating, and pyrolyzing the aerosol droplets. Forming a dry particle aerosol via evaporation of the solvent of the submicron droplet aerosol, and / or The method according to claim 57, further comprising optionally forming a powder of submicron or nanostructured particles by passing the dry particle aerosol through a particle collector.

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