Layered particles and methods thereof

Abstract

Methods for making layered particles are provided. Also provided are layered particles made by such methods.

Description

[Technical field]

[0001] The present disclosure provides small layered particles that may have multiple functionalities, as well as methods for making such particles. [Background technology]

[0002] Small particles have applications in many different industries, including but not limited to the pharmaceutical, food, energy, and fine chemical industries. Such particles, due to their size, can reduce the diffusion limit and therefore allow the particles (bound to molecules of interest) to move more easily across different boundaries. For example, in the pharmaceutical industry, small particles are often used to increase the delivery rate of biologically active ingredients that are otherwise difficult to deliver, including but not limited to hydrophobic drugs that tend to have low solubility in water.

[0003] Furthermore, in some cases, it is useful to encapsulate biologically active ingredients in small particles to protect them until they are in close proximity to their intended biological or molecular target.In such cases, the circumstances and timing of the release of active ingredients must be precisely controlled.Unfortunately, when using conventional encapsulation techniques, active ingredients may prematurely separate from particles and migrate to the surface before reaching biological targets.Due to this tendency, it is necessary to prevent active ingredients from prematurely releasing from small particle carriers in order to preserve the desired biological activity of small particle carriers.

[0004] The delivery of certain biologically active components poses significant challenges, including, but not limited to, DNA, RNA, and RNA interference (RNAi) agents (e.g., small interfering RNA (siRNA) or micro-interfering RNA (miRNA) agents). Recently, there has been great interest in delivering fragments of RNA (including siRNA and miRNA) and DNA for the treatment of various diseases. However, naked RNA and DNA agents can be toxic and are easily attacked by the body's immune system. As a result, in vivo efficacy has not met expectations based on in vitro results, and serious side effects have also been observed.

[0005] In particular, RNA-based therapeutics have attracted significant attention in recent years due to their potential to treat various chronic diseases, such as cardiovascular diseases, kidney diseases, tumors, infectious diseases, inflammatory diseases, and metabolic diseases. The promise of RNA therapeutics is related to their excellent gene silencing potential, high target specificity, and preliminary positive results seen in early-phase clinical trials. In addition, the ease of producing such therapeutics with high purity contributes to their widespread demand. Industry Analysis and Forecast (2014-2020) suggests that the market for RNA-based therapeutics will reach $1.2 billion by 2020, representing a compound annual growth rate of 28.4% from 2014 to 2020. However, unless improved delivery technologies are developed, RNA therapeutics will never reach their full potential.

[0006] RNAi represents a field of RNA therapeutics that would greatly benefit from improved delivery technologies. RNAi was first discovered in plants, but was not widely known in animals until Andrew Fire and Craig Mello demonstrated that double-stranded RNA can suppress gene expression to a greater extent than single-stranded RNA in Caenorhabditis elegans [3]. RNAi methods utilize short nucleotide sequences (e.g., 20-30 nucleotides) that selectively bind to their target messenger RNAs in the RNA-induced silencing complex (RISC) and promote their degradation, thereby reducing the expression of the corresponding genes. Despite the promise of this method, delivering RNAi agents remains a major barrier to the widespread use of RNAi therapeutics in clinical settings.

[0007] Numerous small particle-based formulations have been developed to date, but they suffer from various problems and, as a result, have not been adopted for widespread use. In many cases, the nano- and micron-sized particles in these formulations lack the complex functionality required to survive hostile environments or to function effectively once they successfully reach their target. To achieve the required functionality required for optimal activity, it would be desirable to create layered particles. In theory, particles with one or more layers can be utilized, with each layer providing the particle with different functionality designed for a specific purpose. For example, layered particles can provide protection of active ingredients from oxidation, sequential delivery of multiple active ingredients from a single layer particle, modification of the surface properties of the particle to enhance biocompatibility, or provide stealth in a reactive biological environment.

[0008] Composite lamellar particles clearly require more complex manufacturing processes than those typically used to produce simpler particles. In order for these complex methods to be used on a commercial scale or under the controlled conditions required for pharmaceutical manufacturing, the methods must be efficient, amenable to scale-up, and compliant with current good manufacturing practice (cGMP). One method currently used to produce lamellar particles to deliver biologically active ingredients (including RNA and DNA) uses calcium phosphate. In theory, calcium phosphate is a desirable starting material for biologically active small particles. Calcium phosphate is harmless and already present in the body. In addition, calcium phosphate is positively charged, which matches well with the negative charge of RNA and DNA fragments. However, calcium phosphate particles have significant drawbacks. For example, calcium phosphate particles (1) are notoriously unstable, (2) may not be able to fully encapsulate or fully protect the active agent, and (3) are difficult to manufacture on a large scale or under conditions suitable for pharmaceutical manufacturing. As a result, there have been no clinical studies using micro- or nanoparticle formulations of calcium phosphate to deliver RNA or DNA therapeutics. For the most part, the formulations used by developers of these treatments instead use lipid particles, which have other well-known issues including toxicity from cationic lipids and liver interactions.

[0009] Currently, formulations containing multifunctional particles are mainly based only on surface functionalization, rather than the use of multiple layers. For example, Ferrari [1] describes particles that contain an active ingredient in a polymer matrix. The surface is then functionalized to improve stealth and targeting. However, only one vesicle contains the active ingredient. Such particles are used by several pharmaceutical companies.

[0010] US Patent No. 5,593,875 [2] describes the formation of calcium phosphate particles for transfection. These particles are formed by simply mixing dilute solutions of the reactants. The particles are allowed to grow passively for a period of time, and then the liquid is diluted to stop the growth of the particles while, at the same time, the cells to be transfected are added to the dilute solution. The particles described have several drawbacks: these particles (1) do not have a layer, (2) are produced in a dilute solution, (3) the growth is not easily controlled, and (4) must be used simultaneously with a final dilution that stops the growth. As a result, in addition to being inefficient, this method would not be practical for use in a clinical setting.

[0011] Elizabeth Verena Giger in Reference [4] explores ways to functionalize the surface of calcium phosphate particles to increase their stability, but the particles are produced by uncontrolled mixing of ultra-dilute solutions of the reactants.

[0012] Yang et al. in reference [5] describe a method for preparing calcium phosphate nanoparticles in a water-in-oil emulsion in an organic solvent. However, this method requires the use of large amounts of hazardous solvents and is difficult to scale up.

[0013] There remains a need for new layered particles for delivering active ingredients in a controlled and effective manner. Additionally, there is a continuing need for methods of producing particles that are amenable to scaled-up manufacturing and can be used in the manufacture of pharmaceuticals and other products that require efficient, scalable, and well-controlled manufacturing methods. Summary of the Invention

[0014] The present disclosure addresses the above problems by providing a method for making layered particles.

[0015] Another aspect of the present disclosure provides particles produced by the methods of the present disclosure.Other embodiments are also disclosed.

[0016] The methods of the present disclosure allow one or more layers to be constructed on small particles with precise dimensions. These methods can produce particles with higher concentrations than those using conventional methods, thus increasing the efficiency of the manufacturing process. Furthermore, the methods of the present disclosure can avoid the use of organic solvents and completely encapsulate the active ingredient by creating one or more layers around the particle. Furthermore, the methods of the present disclosure can create one or more layers on the surface of the particle that can modify the surface and release properties of the active ingredient as desired. As a result, the layered particles according to the present disclosure can deliver precise amounts of the active ingredient in a controlled and effective manner.

[0017] The above-mentioned aspects of the embodiments will become more apparent and be better understood by reference to the following description of the embodiments in conjunction with the accompanying drawings. One aspect of the present invention is described below. [Invention 1] 1. A method for producing layered particles, comprising the steps of: (a) forming a first liquid stream comprising: (i) introducing one or more core particles into a first liquid carrier; (ii) mixing the one or more core particles in the first liquid carrier to form a first mixture; (iii) optionally homogenizing the first mixture; and (iv) introducing one or more reactants into said first mixture; (b) forming a second liquid stream comprising: (i) introducing one or more reactants into a second liquid carrier; (ii) mixing the one or more reactants in a second liquid carrier to form a second mixture; and (iii) optionally homogenizing the second mixture; (c) continuously feeding the first liquid stream into a first port of a multi-port mixer, the first liquid stream being fed into the mixer at a rate of the flow rate of the mixer; (d) continuously feeding the second liquid stream into a second port of the multi-port mixer; and (e) mixing the first liquid stream and the second liquid stream in the mixer for an effective period of time to form a layer on the one or more core particles. Equipped with The mixing device provides an average energy ratio of about 10 per kilogram of liquid stream mixture. 3 ~about 10 10 Has the ability to produce W / kg method. [Invention 2] 2. The method of claim 1, wherein step (a)(iv) further comprises introducing one or more surfactants into said first mixture. [Invention 3] 2. The method of claim 1, wherein step (b)(i) further comprises introducing one or more surfactants into said second liquid carrier. [Invention 4] The method of claim 1, wherein step (a) further comprises washing the one or more core particles. [Invention 5] The method according to claim 1, wherein the effective period is from about 1 microsecond to about 1 hour. [Invention 6] 5. The method of claim 4, further comprising suspending the one or more core particles in a solution. [Invention 7] 7. The method of claim 6, further comprising deagglomerating the one or more core particles. [Invention 8] The method according to invention 5, wherein the effective period is from about 1 microsecond to about 20 seconds. [Invention 9] The method according to claim 1, wherein the effective period is from about 1 microsecond to about 1 minute. [Invention 10] 2. The method of claim 1, wherein step (e) further comprises washing the one or more layered particles. [Invention 11] 2. The method of claim 1, further comprising repeating steps (a)(iv) and (b)(iii) through (e) to increase the thickness of the layer. [Invention 12] The method of claim 1, further comprising repeating steps (a)-(e) to form a second layer. [Invention 13] 13. The method of claim 12, further comprising suspending the one or more layered particles in a solution. [Invention 14] 14. The method of claim 13, further comprising deagglomerating the one or more layered particles. [Invention 15] 15. The method of claim 14, further comprising filtering the mixture to remove particles having a size of about 200 nm to about 25 microns. [Invention 16] 15. The method of claim 14, further comprising sterilizing the mixture. [Invention 17] 2. The method of claim 1, further comprising freeze-drying the one or more layered particles. [Invention 18] 2. The method of claim 1, further comprising drying the one or more layered particles. [Invention 19] 2. The method of claim 1, further comprising heat treating the one or more layered particles. [Invention 20] 2. The method of claim 1, wherein the one or more reactants in the first liquid stream is an acid. [Invention 21] 2. The method of claim 1, wherein the one or more reactants in the first liquid stream is a base. [Invention 22] 21. The method of claim 20, wherein the one or more reactants in the second liquid stream is a base. [Invention 23] 22. The method of claim 21, wherein the one or more reactants in the second liquid stream is an acid. [Invention 24] 23. The method of claim 22, wherein the acid and the base react to form a salt. [Invention 25] 24. The method of claim 23, wherein the acid and the base react to form a salt. [Invention 26] 2. The method of claim 1, wherein the reactant in the first liquid stream and the second liquid stream is a salt. [Invention 27] 27. The method of claim 26, wherein said salt reacts to form another salt. [Invention 28] 2. The method according to claim 1, wherein the same liquid is used in the first liquid stream and the second liquid stream. [Invention 29] 2. The method of claim 1, wherein different liquids are used in the first and second liquid streams. [Invention 30] 2. The method of claim 1, wherein the layered particles comprise crystalline solid particles. [Invention 31] The layered particles are amorphous solids. The method of claim 1, further comprising the step of: [Invention 32] 2. The method of claim 1, wherein the layered particles comprise solid, liquid, or semi-solid particles. [Invention 33] 2. The method of claim 1, wherein the lamellar particles comprise particles selected from small molecules, nucleic acids, proteins, peptides, and monoclonal antibodies, and combinations thereof. [Invention 34] The method according to claim 1, wherein one or more active ingredients are encapsulated in the layered particles. [Invention 35] 2. The method of claim 1, wherein one or more active ingredients are embedded in a matrix within the layered particles. [Invention 36] 36. The method of claim 35, wherein the matrix is ​​selected from polymers, metal oxides, organic salts, inorganic salts, lipids, oils, and waxes. [Invention 37] 2. The method of claim 1, wherein the one or more reactants in the first liquid stream react with the one or more reactants in the second liquid stream when the first and second liquid streams are mixed in step (e). [Invention 38] 38. The method of claim 37, wherein the one or more reactants in the first liquid stream and the one or more reactants in the second liquid stream comprise dissolved salts that precipitate when the salts in the first liquid stream and the salts in the second liquid stream contact during mixing step (e). [Invention 39] 39. The method of claim 38, wherein the salt in the first liquid stream comprises calcium chloride or other calcium salts and the salt in the second liquid stream comprises sodium phosphate or other phosphate salts. [Invention 40] 39. The method of claim 38, wherein the salt in the first liquid stream comprises sodium phosphate and the salt in the second liquid stream comprises calcium chloride. [Invention 41] 39. The method of claim 38, wherein the salt in the first liquid stream comprises calcium chloride and the salt in the second liquid stream comprises sodium carbonate. [Invention 42] 39. The method of claim 38, wherein the salt in the first liquid stream comprises sodium phosphate and the salt in the second liquid stream comprises calcium chloride. [Invention 43] 40. The method of claim 39, wherein the first liquid stream, the second liquid stream, or both the first liquid stream and the second liquid stream further comprise nucleic acid. [Invention 44] 41. The method of claim 40, wherein the first liquid stream, the second liquid stream, or both the first liquid stream and the second liquid stream further comprise nucleic acid. [Invention 45] 42. The method of claim 41, wherein the first liquid stream, the second liquid stream, or both the first liquid stream and the second liquid stream further comprise nucleic acid. [Invention 46] 43. The method of claim 42, wherein the first liquid stream, the second liquid stream, or both the first liquid stream and the second liquid stream further comprise nucleic acid. [Invention 47] 40. The method of claim 39, wherein the first liquid stream, the second liquid stream, or both the first liquid stream and the second liquid stream further comprise one or more active pharmaceutical ingredients. [Invention 48] 41. The method of claim 40, wherein the first liquid stream, the second liquid stream, or both the first liquid stream and the second liquid stream further comprise one or more active pharmaceutical ingredients. [Invention 49] 42. The method of claim 41, wherein the first liquid stream, the second liquid stream, or both the first liquid stream and the second liquid stream further comprise one or more active pharmaceutical ingredients. [Invention 50] 43. The method of claim 42, wherein the first liquid stream, the second liquid stream, or both the first liquid stream and the second liquid stream further comprise one or more active pharmaceutical ingredients. [Invention 51] 2. The method of claim 1, wherein the first liquid stream and the second liquid stream are miscible. [Invention 52] 2. The method of claim 1, wherein the first liquid stream and the second liquid stream are immiscible. [Invention 53] 52. The method of claim 51, wherein the liquid carrier in the first liquid stream is a solvent and the liquid carrier in the second liquid stream is an antisolvent. [Invention 54] 52. The method of claim 51, wherein the liquid carrier in the first liquid stream is an antisolvent and the liquid carrier in the second liquid stream is a solvent. [Invention 55] 53. The method of claim 52, wherein the liquid carrier in the first liquid stream is a solvent and the liquid carrier in the second liquid stream is an anti-solvent. [Invention 56] 53. The method of claim 52, wherein the liquid carrier in the first liquid stream is an antisolvent and the liquid carrier in the second liquid stream is a solvent. [Invention 57] 52. The method of claim 51, wherein the liquid carrier in the first liquid stream is aqueous and the liquid carrier in the second liquid stream comprises one or more water-miscible organic solvents having one or more polymers or one or more lipids dissolved in the solvent. [Invention 58] 8. The method of claim 7, wherein the one or more solvents comprise a water-miscible alcohol or a water-miscible ketone. [Invention 59] 58. The method of claim 57, wherein the one or more solvents are selected from ethanol, methanol, acetone, dimethylsulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), tetrahydrofuran, acetonitrile, and poly(ethylene glycol). [Invention 60] 58. The method of claim 57, wherein the one or more polymers are selected from poly(lactic acid) (PLA), poly(lactide-co-glycolide) (PLGA), poly(ε-caprolactone) (PCL), starch, polysaccharides, biocompatible polymers, poly(acrylates), and poly(styrene), and derivatives thereof. [Invention 61] 58. The method of claim 57, wherein the one or more lipids are selected from cholesterol, phospholipids, cationic lipids, neutral lipids, and sterols, and derivatives thereof. [Invention 62] 58. The method of claim 57, wherein the one or more liquids are selected from lipids comprising poly(ethylene glycol) (PEGylated), fluorescent lipids, and cross-linked lipids. [Invention 63] 58. The method of claim 57, wherein the first liquid stream, the second liquid stream, or both the first liquid stream and the second liquid stream further comprise one or more active pharmaceutical ingredients. [Invention 64] 2. The method of claim 1, wherein the layer results from one of precipitation, crystallization, polymerization, crosslinking, acid-base reaction, substitution reaction, oxidation reaction, reduction reaction, adsorption, and chemisorption. [Invention 65] A method for producing core particles, comprising the steps of: (a) forming a first liquid stream comprising: (i) introducing one or more reactants into a first liquid carrier to form a first liquid stream; and (ii) optionally homogenizing the first liquid stream; (b) forming a second liquid stream comprising: (i) introducing one or more reactants into a second liquid carrier to form a second liquid stream; and (ii) optionally homogenizing said second liquid stream; (c) directing said first liquid stream into a first port of a multi-port mixer; (d) directing the second liquid stream into a second port of the multi-port mixer; and (e) mixing the first liquid stream with the second liquid stream to form one or more core particles. Equipped with The mixing device provides an average energy ratio of about 10 per kilogram of liquid stream mixture. 3 ~about 10 10 Has the ability to produce W / kg method. [Invention 66] (a) forming a first liquid stream comprising: (i) introducing said one or more core particles into a first liquid carrier; (ii) mixing the one or more core particles in the first liquid carrier to form a first mixture; (iii) optionally homogenizing the first mixture; and (iv) introducing one or more reactants into said first mixture; (b) forming a second liquid stream comprising: (i) introducing one or more reactants into a second liquid carrier; (ii) mixing the one or more reactants in the second liquid carrier to form a second mixture; and (iii) optionally homogenizing the second mixture; (c) continuously feeding the first liquid stream into a first port of a multi-port mixer, the first liquid stream being fed into the mixer at a rate of the flow rate of the mixer; (d) continuously feeding the second liquid stream into a second port of the multi-port mixer; and (e) mixing the first liquid stream and the second liquid stream in the mixer for an effective period of time to form a layer on the one or more core particles. a step of producing layered particles using the core particles, 66. The method of claim 65, further comprising: The mixing device provides an average energy ratio of about 10 per kilogram of liquid stream mixture. 3 ~about 10 10 Has the ability to produce W / kg method. [Invention 67] 67. The method of claim 66, further comprising washing the one or more layered particles. [Invention 68] 67. The method of claim 66, further comprising repeating steps (a)-(e) to form a second layer. [Invention 69] 1. A layered particle produced by the method according to claim 1. [Invention 70] 66. A core particle produced by the method according to claim 65. [Invention 71] 2. The method of claim 1, wherein the first mixture is selected from a suspension, a solution, and an emulsion. [Invention 72] 2. The method of claim 1, wherein the second mixture is selected from a suspension, a solution, and an emulsion. [Invention 73] 2. The method according to claim 1, wherein the ratio of flow rates of the mixing device is about 0.0001 to about 0.9. [Invention 74] 74. The method according to claim 73, wherein the ratio is about 0.001 to about 0.9. [Invention 75] 67. The method of claim 66, wherein the first mixture is selected from a suspension, a solution, and an emulsion. [Invention 76] 67. The method of claim 66, wherein the second mixture is selected from a suspension, a solution, and an emulsion. [Invention 77] 2. The method according to claim 1, wherein the mixing device is a homogenizer or a rotor-stator mixer. [Invention 78] The method of claim 1, wherein the one or more core particles are present in the liquid stream mixture of step (e) in an amount of about 0.01% to about 50% (weight of the one or more core particles / (weight of the liquid stream mixture of step (e) plus the one or more core particles)). [Invention 79] The method of claim 1, wherein the one or more core particles are present in the liquid stream mixture of step (e) in an amount of about 2% to about 50% (weight of the one or more core particles / (weight of the liquid stream mixture of step (e) plus the one or more core particles)). [Invention 80] The method of claim 1, wherein the one or more core particles are present in the liquid stream mixture of step (e) in an amount of about 5% to about 50% (weight of the one or more core particles / (weight of the liquid stream mixture of step (e) plus the one or more core particles)). [Invention 81] The method of claim 1, wherein the one or more core particles are present in the liquid stream mixture of step (e) in an amount of about 2% to about 40% (weight of the one or more core particles / (weight of the liquid stream mixture of step (e) plus the one or more core particles)). [Invention 82] The method according to claim 1, wherein the homogenization in step 1(a)(iii) and step 1(b)(iii) is carried out at a pressure of about 500 psi to 45,000 psi. [Invention 83] The method according to claim 1, wherein the homogenization in step 1(a)(iii) and step 1(b)(iii) is carried out at a pressure of about 3,000 psi to 30,000 psi. [Invention 84] The method according to claim 1, wherein the mixing device further comprises a processing module. [Invention 85] 85. The method of claim 84, wherein the residence time in the processing module is from about 1 microsecond to about 1 millisecond. [Invention 86] 85. The method of claim 84, wherein the residence time in the processing module is from about 2 microseconds to about 100 microseconds. [Invention 87] 85. The method of claim 84, wherein the residence time in the processing module is from about 10 microseconds to about 90 microseconds. [Invention 88] 85. The method of claim 84, wherein the residence time in the processing module is from about 10 microseconds to about 25 microseconds. [Invention 89] 66. The method of claim 65, wherein the mixing device is a homogenizer or a rotor-stator mixer. [Invention 90] 2. The method according to claim 1, wherein the layered particles have an average particle size of about 1 to about 300 nanometers. [Invention 91] 67. The method of claim 66, wherein the layered particles have an average particle size of about 1 to about 300 nanometers. [Invention 92] 35. The method of claim 34, wherein the one or more active ingredients are active pharmaceutical ingredients. [Brief description of the drawings]

[0018] [Figure 1] 1 illustrates a layered particle according to one embodiment. [Diagram 2] 1 illustrates a layered particle according to one embodiment. [Diagram 3] 1 illustrates a layered particle according to one embodiment. [Figure 4] 1 illustrates a layered particle according to one embodiment. [Diagram 5] 1 illustrates a layered particle according to one embodiment. [Figure 6] 1 illustrates a method for making layered particles according to one embodiment. [Figure 7A] 1 illustrates a portion of a method for making layered particles according to one embodiment. [Figure 7B] 1 illustrates a portion of a method for making layered particles according to one embodiment. [Figure 8A] 1 illustrates a portion of a method for making layered particles according to one embodiment. [Figure 8B] 1 illustrates a portion of a method for making layered particles according to one embodiment. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] The embodiments described below are not intended to be exhaustive or to limit the invention to the precise forms disclosed in the following detailed description. Rather, the embodiments are chosen and described so that others skilled in the art can appreciate and understand the principles and practices of the present disclosure.

[0020] One aspect of the present disclosure provides a method for producing layered particles. In some embodiments, the method comprises: (a) forming a first liquid stream comprising: (i) introducing one or more core particles into a first liquid carrier; (ii) mixing one or more core particles in a first liquid carrier to form a first mixture; (iii) optionally homogenizing the first mixture; and (iv) introducing one or more reactants into the first mixture; (b) forming a second liquid stream comprising: (i) introducing one or more reactants into a second liquid carrier; (ii) mixing one or more reactants in a second liquid carrier to form a second mixture; and (iii) optionally homogenizing the second mixture; (c) continuously feeding a first liquid stream into a first port of a multi-port homogenizer, rotor stator mixer, or microreactor, the first liquid stream being fed into the homogenizer, rotor stator mixer, or microreactor at a rate of the homogenizer, rotor stator mixer, or microreactor flow rate; (d) continuously feeding the second liquid stream into a second port of the multi-port homogenizer, rotor-stator mixer, or microreactor; and (e) mixing the first liquid stream and the second liquid stream in a homogenizer, rotor-stator mixer, or microreactor for an effective period of time to form a layer on the one or more core particles.

[0021] In some embodiments, step (a)(iv) further comprises introducing one or more surfactants to the first mixture. In some embodiments, step (b)(i) further comprises introducing one or more surfactants to the second liquid carrier. In some embodiments, step (a) further comprises washing the one or more core particles. As used herein, the term "layered particle" refers to a core particle having one or more layers.

[0022] In some embodiments, step (b) further comprises washing the one or more core particles.

[0023] As used herein, the term "effective period" refers to the period during which the first and second liquid streams are thoroughly mixed to form a layer on one or more core particles. In some embodiments, the effective period is from about 1 microsecond to about 1 hour. In other embodiments, the effective period is from about 1 microsecond to about 20 seconds. In other embodiments, the effective period is from about 1 microsecond to about 1 minute. In other embodiments, the effective period is from about 1 microsecond to about 100 microseconds. In some embodiments, the effective period is from about 10 microseconds to about 90 microseconds.

[0024] In some embodiments, the method of the present disclosure further comprises suspending one or more core particles in a solution. In some embodiments, the method of the present disclosure further comprises deagglomerating one or more core particles. In some embodiments, the method further comprises suspending one or more layered particles in a solution. In some embodiments, the method of the present disclosure further comprises deagglomerating one or more layered particles.

[0025] In some embodiments, step (e) further comprises washing the one or more layered particles. In some embodiments, the method of the present disclosure further comprises repeating steps (a)(iv) and (b)(iii) through (e) to increase the thickness of the layer. In some embodiments, the method of the present disclosure further comprises repeating steps (a) through (e) to form a second layer.

[0026] In some embodiments, the method of the present disclosure further comprises suspending one or more layered particles in a solution. In some embodiments, the method of the present disclosure further comprises deagglomerating one or more layered particles. In some embodiments, the method of the present disclosure further comprises filtering the mixture to remove particles having a size of about 200 nm to about 25 microns.

[0027] In some embodiments, the methods of the present disclosure further comprise sterilizing the mixture.

[0028] In some embodiments, the methods of the present disclosure further comprise freeze-drying one or more layered particles. In some embodiments, the methods of the present disclosure further comprise drying one or more layered particles. In some embodiments, the methods of the present disclosure further comprise heat-treating one or more layered particles.

[0029] In some embodiments, one or more reactants in the first liquid stream are acids. In some embodiments, one or more reactants in the first liquid stream are bases. In some embodiments, one or more reactants in the second liquid stream are bases. In some embodiments, one or more reactants in the second liquid stream are acids. In some embodiments, an acid and a base react to form a salt. In some embodiments, reactants in the first and second liquid streams are salts. In some embodiments, salts react to form other salts.

[0030] In some embodiments, the same liquid is used in the first and second liquid flows. In some embodiments, different liquids are used in the first and second liquid flows. In some embodiments, the layered particles comprise crystalline solid particles. In some embodiments, the layered particles comprise amorphous solid particles. In some embodiments, the layered particles comprise solid, liquid, or semi-solid particles.

[0031] In some embodiments, the lamellar particles are selected from small molecules, nucleic acids, proteins, peptides, and monoclonal antibodies. In some embodiments, one or more active pharmaceutical ingredients are encapsulated in the lamellar particles. In some embodiments, one or more active pharmaceutical ingredients are embedded in a matrix within the lamellar particles. In some embodiments, the matrix is ​​selected from polymers, metal oxides, organic salts, inorganic salts, lipids, oils, and waxes.

[0032] In some embodiments, one or more of the core particles or one or more of the layers include, but are not limited to, one or more of the following or derivatives thereof: a) Polymers: poly(lactic acid) (PLA), poly(lactide-co-glycolide) (PLGA), poly(ε-caprolactone) (PCL), starch, polysaccharides, biocompatible polymers, poly(acrylates), and poly(styrene), cross-linked polymers, alginates, polymers including PES (PEGylated polymers), and their derivatives; b) Lipids: cholesterol, phospholipids, lecithin, soy lecithin, egg lecithin, cationic lipids, neutral lipids, and sterols and their derivatives. In some embodiments, the one or more lipids are selected from lipids containing poly(ethylene glycol) (PEGylated), fluorescent lipids, and cross-linked lipids; c) gelatin, sucrose, dextrose, RNA, DNA, nucleic acid containing species, peptides, proteins, monoclonal antibodies, small molecule drugs, curcumin, plant sterols, carotenoids, and vitamin C; d) vegetable oils, soybean oil, olive oil, canola oil, corn oil, palm oil, sesame oil, vitamin E, nut oils, fish oils, omega-3 containing oils, monoglycerides, oligoglycerides, polyglycerides, vitamin A, vitamin K, oleic acid, mineral oil, squalene, squalene, essential oils, waxes, perfluorocarbons, perfluorodecalene, and FC-43; e) sodium chloride, sodium carbonate, sodium phosphate, sodium salts, calcium carbonate, calcium phosphate, calcium salts, magnesium phosphate, aluminosilicates, silica, alumina, zirconia, metal oxides, barium titanate, PZT (lead zirconate titanate), carbon, graphite, glassy carbon, amorphous carbon, gold, silver, platinum, palladium, metal particles, and derivatives thereof; f) anti-cancer drugs, antibiotics, anesthetics, anti-inflammatory drugs, ophthalmic drugs, vaccines, adjuvants, and analgesics; and g) Polysorbates, Tween 80, Tween 20, Tween 60, polyoxyethylene octylphenyl ether, Triton-X100, Igepal CA-630, various Kolliphor™ materials, Soluplus®, Collidon®, Span® 85, sorbitan trioleate, albumin, whey protein, xanthan gum, and derivatives thereof.

[0033] In some embodiments, the first liquid carrier includes, but is not limited to, water, buffer, ethanol, methanol, acetone, dimethylsulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), tetrahydrofuran, acetonitrile, poly(ethylene glycol), dichloromethane, heptane, and other limonene and 2-methyltetrahydrofuran (2-MeTHF), glycerol, and derivatives and combinations thereof.

[0034] In some embodiments, the one or more reactants include, but are not limited to, calcium chloride, calcium carbonate, calcium hydroxide, sodium phosphate, sodium carbonate, calcium nitrate, sodium hydroxide, magnesium hydroxide, sodium silicate, aluminum, aluminum sulfate, benzoyl peroxide, ammonia, nitric oxide, stearic acid, hydrochloric acid, sulfuric acid, silica, zinc nitrate, furfuryl alcohol, zinc parathion, and zirconium oxychloride.

[0035] In some embodiments, the second liquid carrier includes, but is not limited to, water, buffer, ethanol, methanol, acetone, dimethylsulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), tetrahydrofuran, acetonitrile, poly(ethylene glycol), dichloromethane, heptane and other limonenes, and 2-methyltetrahydrofuran (2-MeTHF), glycerol, and derivatives and combinations thereof.

[0036] In some embodiments, when the first and second liquid streams are mixed in step (e), one or more reactants in the first liquid stream react with one or more reactants in the second liquid stream. In some embodiments, one or more reactants in the first liquid stream and one or more reactants in the second liquid stream comprise dissolved salts that precipitate when a salt in the first liquid stream and a salt in the second liquid stream contact each other during the mixing step (e).

[0037] In some embodiments, the salt in the first liquid stream comprises calcium chloride or any other calcium salt and the salt in the second liquid stream comprises sodium phosphate or any other phosphate salt, In some embodiments, the salt in the first liquid stream comprises sodium phosphate and the salt in the second liquid stream comprises calcium chloride.

[0038] In some embodiments, the first liquid stream, the second liquid stream, or both the first and second liquid streams further comprise nucleic acid.

[0039] In some embodiments, the first liquid stream, the second liquid stream, or both the first and second liquid streams further comprise one or more active pharmaceutical ingredients.

[0040] In some embodiments, the first liquid carrier and the second liquid carrier are the same.

[0041] In some embodiments, the energy ratio of mixing in step (e) is about 10 to about 10 10 W / kg.

[0042] In some embodiments, the first and second liquid streams are miscible. In some embodiments, the first and second liquid streams are immiscible. In some embodiments, the liquid carrier in the first liquid stream is a solvent and the liquid carrier in the second liquid stream is an anti-solvent. In some embodiments, the liquid carrier in the first liquid stream is an anti-solvent and the liquid carrier in the second liquid stream is a solvent.

[0043] In some embodiments, the liquid carrier in the first liquid stream is a solvent and the liquid carrier in the second liquid stream is an antisolvent. In some embodiments, the liquid carrier in the first liquid stream is an antisolvent and the liquid carrier in the second liquid stream is a solvent. In some embodiments, the liquid carrier in the first liquid stream is aqueous and the liquid carrier in the second liquid stream comprises one or more water-miscible organic solvents having one or more polymers or one or more lipids dissolved in the solvent.

[0044] In some embodiments, the one or more solvents include a water-miscible alcohol or a water-miscible ketone. In some embodiments, the one or more solvents are selected from ethanol, methanol, acetone, dimethylsulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), tetrahydrofuran, acetonitrile, and poly(ethylene glycol). In some embodiments, the one or more polymers are selected from poly(lactic acid) (PLA), poly(lactide-co-glycolide) (PLGA), poly(ε-caprolactone) (PCL), starch, polysaccharides, biocompatible polymers, poly(acrylates), and poly(styrene), and derivatives thereof.

[0045] In some embodiments, the one or more lipids are selected from cholesterol, phospholipids, cationic lipids, neutral lipids, and sterols, and derivatives thereof. In some embodiments, the one or more lipids are selected from lipids comprising poly(ethylene glycol) (PEGylated), fluorescent lipids, and cross-linked lipids.

[0046] In some embodiments, the first liquid stream, the second liquid stream, or both the first and second liquid streams further comprise one or more active pharmaceutical ingredients. In some embodiments, the layer results from one of precipitation, crystallization, polymerization, crosslinking, acid-base reaction, substitution reaction, oxidation reaction, reduction reaction, adsorption, and chemisorption.

[0047] In some embodiments, the first mixture is selected from a suspension, a solution, and an emulsion. In some embodiments, the second mixture is selected from a suspension, a solution, and an emulsion.

[0048] In some embodiments, the ratio of the flow rates of the homogenizer, rotor-stator mixer, or microreactor is from about 0.0001 to about 0.9. In some embodiments, the ratio is from about 0.001 to about 0.9.

[0049] Another aspect of the present disclosure provides a method for producing layered particles comprising: (a) mixing a liquid medium containing core particles with a liquid carrier to form a mixture; (b) homogenizing the mixture to deagglomerate the core particles; (c) separating the mixture into a first liquid stream and a second liquid stream; (d) introducing one or more reactants into the first liquid stream and one or more reactants into the second liquid stream; (e) mixing or homogenizing the first liquid stream and the second liquid stream to react and form a layer;

[0050] In some embodiments, the liquid medium further comprises a surfactant. In some embodiments, step (e) further comprises washing the layered particles. In some embodiments, the method of the present disclosure further comprises repeating steps (a)-(e) to form a second layer.

[0051] In some embodiments, the same core particles, reactants, and liquid carriers are utilized. In some embodiments, different core particles, reactants, and liquid carriers are utilized.

[0052] In some embodiments, the method of the present disclosure further comprises suspending the lamellar particles in a solution. In some embodiments, the method of the present disclosure further comprises filtering the mixture to remove particles having a size of about 200 nm to about 25 microns. In some embodiments, the method of the present disclosure further comprises sterilizing the mixture.

[0053] In some embodiments, the methods of the present disclosure further comprise freeze-drying the layered particles. In some embodiments, the methods of the present disclosure further comprise drying the layered particles. In some embodiments, the methods of the present disclosure further comprise heat-treating the layered particles.

[0054] Another aspect of the present disclosure provides a method for producing layered particles comprising: (a) forming a first liquid stream comprising: (i) introducing one or more core particles into a first liquid carrier; (ii) mixing one or more core particles in a first liquid carrier to form a first mixture; (iii) optionally homogenizing the first mixture; and (iv) introducing one or more reactants into the first mixture; (b) forming a second liquid stream comprising: (i) introducing one or more core particles into a second liquid carrier; (ii) mixing one or more core particles in a second liquid carrier to form a second mixture; (iii) optionally homogenizing the second mixture; and (iv) introducing one or more reactants into the second mixture; and (c) mixing the first liquid stream with the second liquid stream to form a layer on the one or more core particles.

[0055] In some embodiments, step (a)(iv) further comprises introducing one or more surfactants to the first mixture. In some embodiments, step (b)(iv) further comprises introducing one or more surfactants to the second mixture. In some embodiments, step (c) further comprises washing the one or more core particles. In some embodiments, the method of the present disclosure further comprises repeating steps (a)(iv) and (b)(iv) through (c) to increase the thickness of the layer. In some embodiments, the method of the present disclosure further comprises repeating steps (a) through (c) to form a second layer.

[0056] Another aspect of the present disclosure provides a method for producing a core particle, comprising: (a) forming a first liquid stream comprising: (i) introducing one or more reactants into a first liquid carrier to form a first liquid stream; (ii) optionally homogenizing the first liquid stream; (b) forming a second liquid stream comprising: (i) introducing one or more reactants into a second liquid carrier to form a second liquid stream; and (ii) optionally homogenizing the second liquid stream; (c) directing the first liquid stream into a first port of a multi-port homogenizer, rotor-stator mixer, or microreactor; (d) feeding the second liquid stream into a second port of the multi-port homogenizer, rotor-stator mixer, or microreactor; and (e) mixing the first liquid stream with the second liquid stream to form one or more core particles.

[0057] In some embodiments, the methods of the present disclosure utilize core particles to produce layered particles comprising: (a) forming a first liquid stream comprising: (i) introducing one or more core particles into a first liquid carrier; (ii) mixing one or more core particles in a first liquid carrier to form a first mixture; (iii) optionally homogenizing the first mixture; and (iv) introducing one or more reactants into the first mixture; (b) forming a second liquid stream comprising: (i) introducing one or more reactants into a second liquid carrier; (ii) mixing one or more reactants in a second liquid carrier to form a second mixture; and (iii) optionally homogenizing the second mixture; (c) continuously feeding a first liquid stream into a first port of a multi-port homogenizer, rotor stator mixer, or microreactor, the first liquid stream being fed into the homogenizer, rotor stator mixer, or microreactor at a rate of the homogenizer, rotor stator mixer, or microreactor flow rate; (d) continuously feeding the second liquid stream into a second port of the multi-port homogenizer, rotor-stator mixer, or microreactor; and (e) mixing the first liquid stream and the second liquid stream in a homogenizer, rotor-stator mixer, or microreactor for an effective period of time to form a layer on the one or more core particles.

[0058] In some embodiments, the methods of the present disclosure further comprise washing one or more layered particles. In some embodiments, the methods of the present disclosure further comprise repeating steps (a)-(e) to form a second layer.

[0059] One of ordinary skill in the art will appreciate that the steps in the methods of the present disclosure may be performed in any order. The order of steps will vary depending on the conditions desired by the artisan.

[0060] Another aspect of the present disclosure provides layered particles produced by the methods of the present disclosure.

[0061] Another aspect of the present disclosure provides core particles produced by the methods of the present disclosure.

[0062] In another embodiment of the present disclosure, the mixing energy is controlled by the pressure of the homogenizer, rotor stator mixer or microreactor and the type of processing module. For homogenizers, rotor stator mixers and microreactors, the mixing energy is controlled by the pressure of the homogenizer, rotor stator mixer and microreactor. 5 ~about 10 10 Energy levels in the range of 10 to about 10 W / kg are typical. In some embodiments, the energy levels are from 10 to about 10 10 W / kg.

[0063] In other embodiments of the present disclosure, the contact time of the two streams can vary from about 2 to about 100 microseconds to about 0.5 to about 100 seconds. The exact contact time depends on various factors such as the type of homogenizer, rotor-stator mixer, or microreactor used. U.S. Patent No. 5,187,554

[10] supports contact times in the range of 0.5 to 20 seconds. When a high-pressure homogenizer is used, contact times in the high-energy zone tend to be similar (e.g., about 2 to about 100 microseconds).

[0064] The layered particles formed by the methods of the present disclosure have a variety of characteristics, and for illustrative purposes, the figures show only certain characteristics of particles made by different embodiments of the methods of the present disclosure.

[0065] Figure 1 illustrates a layered particle 10 according to one embodiment. The layered particle 10 includes a core 14 having a coating layer 12. The layered particle 10 can be a solid, liquid, or semi-solid.

[0066] 2 illustrates a layered particle 16 according to one embodiment. Layered particle 16 includes a core 14 having coating layer 12 and coating layer 18. Coating layer 12 surrounds core 14, and coating layer 18 surrounds coating layer 12. Layered particle 16 can be solid, liquid, or semi-solid.

[0067] 3 illustrates a layered particle 20 according to one embodiment. The layered particle 20 comprises a core 14, a coating layer 12, and a matrix containing an active ingredient 22 embedded or dissolved within the core 14.

[0068] 4 illustrates a layered particle 24 according to one embodiment. The layered particle 24 includes a core 14, a coating layer 12, and a crystalline material 26.

[0069] 5 illustrates a layered particle 28 according to one embodiment. The layered particle 28 includes a core 14, a coating layer 12, and a polyethylene glycol 30.

[0070] 6 illustrates a method 32 for making layered particles, in which a liquid stream 34 containing core particles 106 is mixed with a liquid stream 36 under controlled mixing conditions 38 and for a controlled time 40 to produce layered particles 42.

[0071] 7A shows a portion of a method 44 for making layered particles according to one embodiment. Step 46 comprises selecting reactants, liquid carriers, and surfactants for forming core particles. Step 48 comprises forming two or more different reactant liquid streams. Step 50 comprises setting a multi-port mixer for processing the liquid streams from step 48. Step 52 comprises processing the liquid streams to form core particles. Step 54 is an optional step for isolating and washing the core particles. Step 56 is an optional step for suspending and deagglomerating the core particles from step 54. Step 58 comprises selecting reactants for the first layer. Step 60 comprises forming two or more different reactant liquid streams.

[0072] FIG. 7B illustrates a portion of a method 44 for making layered particles according to one embodiment. Beginning after step 60 shown in FIG. 7A, step 62 comprises setting up a multi-port homogenizer to process the liquid stream. Step 64 comprises processing the liquid stream from step 60 to form a layer on the particles. Step 66 is an optional step of isolating and washing the particles. Step 68 is an optional step of repeating steps 60-66 to increase the thickness of the layer. Step 70 is an optional step of repeating steps 58-66 to create another layer of a different material. Step 72 is an optional step of suspending and deagglomerating the particles from any one of steps 66-70. Step 74 is an optional step of filtering the suspension from any one of steps 64-72 to remove large particles or sterilizing the suspension. Step 76 is an optional step of freeze-drying, drying, or otherwise heat-treating the particles from any one of steps 64-72.

[0073] 8A shows a portion of a method 78 for producing layered particles according to one embodiment. Step 80 comprises selection of materials such as core particles, reactants, surfactants, and liquid carriers as further described in this disclosure. Step 82 comprises introducing the core particles into a liquid stream. Step 84 comprises rotor-stator or homogenizer mixing to create a coarse dispersion. Step 86 comprises high pressure homogenization to deagglomerate the particles. Step 88 comprises forming two or more different reactant liquid streams. Step 90 comprises setting a multi-port mixer to process the liquid streams. Step 92 comprises processing the two or more liquid streams from step 90 with the multi-port mixer.

[0074] FIG. 8B shows a portion of a method 78 for producing layered particles according to one embodiment. Starting with the particles produced in FIG. 8A, step 94 is an optional step of isolating and washing the particles. Step 96 is an optional step of repeating steps 82-94 to increase the thickness of the layer using the same material. Step 98 is an optional step of repeating steps 80-94 to create another layer of a different material. Step 100 is an optional step of repeating steps 82-94 to suspend the particles from step 94 in a final solution. Step 102 is an optional step of filtering the suspension from any of steps 92 or 96-100 to remove large particles or to sterilize the suspension. Step 104 is an optional step of freeze-drying, drying, or otherwise heat-treating the particles from any one of steps 92-100.

[0075] The present disclosure also provides various methods for the manufacture of layered particles. The methods of the present disclosure affect key parameters and sub-methods that control the formation of layered particles, including (a) deagglomeration of the core particles to expose their surfaces, and (b) proceeding in a manner that leads to layer formation (such as chemical reaction or precipitation) occurring on the particle surface, rather than occurring independently of the particle. The following exemplary steps are typical for the methods of the present disclosure, but are in no way meant to be limiting.

[0076] 1. Appropriate materials: the core particles, the reactants used to form the next particle layer, and the carrier liquid in each stream are selected. The core particles can be commercially available or previously made. With regard to the reactants, for example, one is an acid and the other is a base, and upon reaction they form a salt. The reactants can also be two salts that react via a substitution reaction to produce a third salt. There are other options that involve physical methods such as precipitation or crystallization rather than chemical reactions. For example, one stream may contain a polymer dissolved in a solvent. The other stream may contain a liquid that is miscible with the solvent, but that does not dissolve the polymer. When these streams are combined, the solubility of the polymer decreases. This may cause the polymer to precipitate. The crystallization method, when the dissolved material crystallizes, is similar to precipitation described above. There can be multiple reactants per stream. The carrier liquids are selected so that they are compatible and typically (but not always) miscible. These carrier liquids can be aqueous solutions with various pHs, organic solvents, or combinations thereof. They may optionally contain surfactants.

[0077] 2. The core particles are mixed in a liquid medium. Typical concentrations of particles in the liquid range from about 0.01 to about 10% by weight, although particle concentrations can approach about 50% depending on the materials involved. Optionally, one or more surfactants are mixed into the solution.

[0078] 3. A rotor-stator mixer is used to create a coarse dispersion. For example, an IKA mixer (IKA Works, Inc., 2635 Northchase Parkway SE, Wilmington, NC 28405, USA) can be used, or a single rotating propeller immersed in the suspension can be used. This process may not completely deagglomerate the liquid, but may create a suspension that can be further processed. For rotor-stator mixers, the important processing parameters are the rotation speed and the type of processing module. While speeds in the range of 500-18,000 rpm are typical, the processing module is selected to suit the processing dispersion, based on the manufacturer's suggestions.

[0079] 4. High pressure homogenization of the coarse suspension. First, the coarse suspension is poured into the inlet vessel of the high pressure homogenizer (HPH). The pressure is typically selected to be in the range of about 3000 to about 30,000 psi, but it can range from about 500 psi to about 45,000 psi or more. The type of processing module of the homogenizer is selected to be suitable for processing the dispersion. The processing module can be, for example, a homogenization valve (APV, Niro Soavi, etc.), a reaction chamber (DyHydromatics) or an interaction chamber (Microfluidics) based on the type of HPH. The outlet temperature of the processed product is controlled by a heat exchanger that is typically located after the processing module. The material can be recirculated several times until deagglomeration is complete, which can be confirmed using a particle size analyzer, optical microscope, or other means known to those skilled in the art.

[0080] 5. Form two different liquid streams. The first stream is a suspension in which one or more reactants are dissolved. The other stream contains another reactant or reactants dissolved in a liquid miscible with the liquid of the first stream. The concentration of the reactants can be predetermined based on the reaction type, reaction rate, and the desired thickness of the layer. Each liquid stream is directed to one port of a two-port mixer and fed in a predetermined ratio. Depending on the application, there are various mixers that can be used. For example, one is described in T. Panagiotou, S. Mesite, R. Fisher, and I. Gruverman, "Production of Stable Drug Nanospensions Using Microfluidics Reaction Technology". NSTI-Nanotech 2007, www.nsti.org, ISBN 1420063766, Vol. 4, pp. 246-249, 2007, which is incorporated herein by reference in its entirety. One such device is essentially a dual port homogenizer and is commercially available (model CR5 from Microfluidics, Westwood, Mass.), as well as dual feed rotor stator mixers from Quadro Engineering, Ontario, Canada.

[0081] Additionally, non-commercially available technology from Microfluidics (MMR) may also be used. Low energy Microfluidics reactors such as those from Precision Nanosystems (Vancouver, BC, Canada) may also be used in some circumstances.

[0082] 6. Set up the machine. Assuming a dual port homogenizer is used as in step 3, the pressure, process module and temperature are selected. Additionally, the flow rate of one of the streams is controlled using a pump. As the total flow rate of the machine is controlled by the pressure and process module, the flow rate of the second stream regulates itself, so that the sum of the flow rates of the two streams is equal to the total flow rate of the machine. The ratio of the flow rates of the two streams controls the stoichiometry of the chemical reaction of the physical process and therefore the reaction rate.

[0083] 7. Create the layers. The HPH machine is turned on and the flows are mixed and allowed to react for a predefined period of time, typically about 1 second in total, as they pass through the treatment module. The residence time in the high energy zone of the treatment module is calculated to be about 10-25 microseconds. Since the chemical reactions / physical processes are completed within these time scales and within the microliter volume of the treatment module, the particles are in close proximity to the reactants and subsequently the reaction products. In addition, the processes are facilitated due to their small scale (as demonstrated in previous studies, see e.g., refs. [7]-[9]). The concentration of the reactants, the pressure, the residence time, the number of passes through the machine, and the initial particle size determine the thickness of each layer. Typical thicknesses are about 1-10 nm for particles with an initial size of less than 500 nm.

[0084] 9. Optionally, isolate and wash the particles. It may be necessary to wash the particles between fabrication layers to remove reactants and impurities from the previous process. One way to wash them would be to filter the particles and then wash the particles captured on the filter with a clean solution. Another method would be to use a centrifuge to separate the particles and then wash them with a clean solution. Yet another method would be to separate the impurities using hollow fiber tangential filtration. This works best for relatively high molecular weight materials including proteins, RNA, DNA, peptides, etc. Optionally, the thickness of the layers can be increased by repeating steps 5-8.

[0085] 10. Optionally, steps 4 through 8 or 9 are repeated to create other layers of the same or different material.

[0086] 11. Optionally, repeat steps 1-3 to suspend particles from step 8 or 9 in the final solution.

[0087] 12. Optionally, filter the suspension to remove large particles, or filter sterilize the suspension using known filtration methods.

[0088] 13. Optionally, the particles are lyophilized using methods known to those of skill in the art.

[0089] In addition to the general method steps outlined above, the present disclosure includes variations on the method that would be known to one of ordinary skill in the art. Such variations include, but are not limited to, the following: (a) Core particles are formed using step 5 and the dual feed device also described in publications [6]-[9] and prior microfluidics US Patent No. 8,187,554. These core particles can consist of solid, liquid or semi-solid materials. The following is an example: As described in reference

[11] , solid polymer particles, optionally containing an active ingredient, are formed by solvent-antisolvent precipitation. These form the core particles, while the layer is formed at a later stage. The function of the layer may be to prevent the active ingredient from leaching out of the particle prematurely. (b) Form the core particle simultaneously with at least one layer. For example, starting from step 4, select reactants using both the core particle and the first layer. If the core particle is formed by a faster method than that required for the first layer, the core particle will be formed first and the layer material will cover the particle. The following is an example: Liquid particles (droplets) in a liquid medium forming an emulsion are produced by separately injecting two liquid and immiscible streams, one of which forms the discontinuous phase of the emulsion and the other the continuous phase, as described in reference [8]. One liquid stream may contain a polymer, which upon precipitation creates a coating around the droplets, forming nanocapsules. (c) More than two liquid reactant streams are used in step 4 to create a coating around the particles. This is useful when multiple processes are being performed and reactants need to be kept separate.

[0090] The particles resulting from the above process variations may have different morphologies. Some of these morphologies are shown in the accompanying drawings for illustrative purposes only. For example, FIG. 1 shows a spherical core particle surrounded by a monolayer. The core particle may be solid, liquid or semi-liquid. Polymeric solid spherical core particles may be produced by micro- or nanoprecipitation of the polymer in a liquid, see reference

[11] . They may also be produced as a result of emulsion polymerization or spray drying, see for example US Pat. No. 5,269,980.

[0091] These layers may act as barriers to prevent certain components of the particle from being released from the particle or slow their release rate. In certain applications, it may be necessary to coat the particle with a layer having certain electrical or electronic properties. As an example, PZT (Lead Zirconate Titanate) is a piezoelectric material used in ultrasonic transducers and piezoelectric resonators. In such applications, it may be desirable to utilize particles coated with a PZT layer. The following references describe the wet chemistry and process for producing PZT: "Low Temperature Synthesis of Stoichiometric and Homogeneous Lead Zirconate Titanate Powders by Oxalate and Hydroxide Coprecipitation", B. Guiffard and M. Troccaz Materials Research Bulletin Volume 33, Issue 12, December 1998, Pages 1759-1768. In this case, the coprecipitation is followed by a heat treatment step.

[0092] During emulsification, liquid particles may be formed. The solid layer around these particles may protect the components of the liquid particles from oxidation, reduce odor, or prevent the components from leaching out. Similarly, the layer around semi-liquid particles, which often contain lipids, may protect the compounds inside the particle.

[0093] Figure 2 shows a particle with multiple layers. Each layer can have a different function. For example, for pharmaceutical applications, the first layer can be used to protect a specific compound inside the core particle. The second layer can be used to create a highly biocompatible surface so that the particle is accepted by the immune system and not attached.

[0094] The core particle in Figure 3 consists of a matrix in which one or more materials are embedded or dissolved. An example would be a polymer particle in which an active ingredient is dissolved or embedded, as mentioned in the previous paragraph. Another example would be a salt such as calcium phosphate containing RNA, DNA or peptide molecules. Another example would be sodium carbonate particles containing protein molecules.

[0095] Figure 4 shows a core particle that is made of crystalline material and is typically not round in shape. Examples of such materials include solid small molecule drugs such as paclitaxel, which are used to treat cancer.

[0096] Figure 5 shows a layered particle with PEG species surrounding the particle. Such species are used to stabilize the particle and form a covert surface so that the particles for pharmaceutical applications are not detected by the body's immune system.

[0097] A common method of deagglomerating particles is to suspend them in various liquids, optionally adding a surfactant, and then apply shear forces to the particles using high energy devices. The shear forces help separate the particles from one another, while the presence of the surfactant helps keep the particles apart for extended periods of time. As will be discussed later in this section, the smaller the particles, the higher the shear forces required. Commonly used techniques for deagglomerating particles include high pressure homogenizers (HPH) and ultrasonicators.

[0098] Once the particles are deagglomerated, they become covered immediately. One or more reactants that form the coating are mixed with the particle suspension. This forms a first liquid stream. Then another liquid stream is formed. The second liquid stream contains a reactant that reacts with the reactant in the first liquid stream. The reactants may undergo a chemical reaction to form another species. For example, one may be an acid and the other a base, and when they react, they form a salt. The reactants may also be two salts that react via a substitution reaction to give a third salt. There are other options that involve physical methods such as precipitation or crystallization rather than chemical reactions. For example, one stream may contain a polymer dissolved in a solvent. The other stream may contain a liquid that is miscible with the solvent, but that does not dissolve the polymer. When these streams meet, the solubility of the polymer decreases. This may cause the polymer to precipitate. However, unless a chemical reaction or physical method is carried out under controlled conditions and with precise timing, the polymer cannot precipitate on the particles or coat each particle with a thin layer. This can be achieved by using appropriate equipment that allows mixing the two streams with the high energy required to form a thin layer around the particle. Furthermore, the mixing time will have to match the time scale of the chemical reaction or physical process.

[0099] The core particles, which act as the base for the multi-layer particles, can be separated from each other to expose the surface area to be coated. Nano- and micron-sized particles have high surface energy and tend to aggregate or conglomerate, which is generally achieved by using surfactants and applying shear to the liquid to disperse the core particles. The level of shear (energy) required also depends on the type and amount of surfactant.

[0100] In some embodiments, shear can occur as a result of the kinetic energy of a liquid as it flows through a pipe, orifice, channel, etc. The liquid is pressurized (potential energy), and as the liquid flows, the potential energy is converted to kinetic energy. In some embodiments, sonication can be used as the energy source. In some embodiments, shear occurs as a result of small gas bubbles moving at high speeds and bursting in the liquid.

[0101] To form a coating on the core particle, the reactants must react at the surface of the core particle, or the reactants react in the liquid but precipitate on the surface of the core particle. If neither of these situations is true, the reaction products will form particles in a manner independent of the core particle.

[0102] In order for the reactants to react on the surface of the particle, one of the reactants can be part of the surface of the core particle. In some embodiments, the surface can catalyze the reaction. If the reaction occurs in the liquid phase, after the product forms, it will have to cover the surface very quickly before the product grows into a large independent particle. Therefore, it is important that the reactants mix on a scale smaller than the core particle so that the reactants react to form small structures that ultimately form the coating. The timing of the mixing of the reactants in relation to the reaction rate is also important.

[0103] When dealing with small particles suspended in a liquid, deagglomeration requires a certain amount of energy. A first approximation is given by turbulence theory, which is used to estimate this from the mixing power input, solution density and viscosity. See, for example, Kolmogorov A. N. The Local Structure of Turbulence in Incompressible Viscous Fluid for Very Large Reynolds Numbers. Proc. USSR Acad. Sci. 1941; 30, 299-303.

number

[0104] where v is the dynamic viscosity and ε is the rate of energy dissipation per unit mass in turbulent mixing. The Kolmogorov length λ is a length scale related to the size of the smallest eddy that can form before heat is dissipated, and the size of the objects that are formed, which also has a large impact on the time scale of the transport processes involved. This equation shows that the smaller the particles, the greater the energy required.

[0105] A common method for deagglomerating particles suspended in a liquid is to use high pressure homogenization (HPH) or microfluidization methods. Equipment for these methods is commercially available from companies such as Niro Soavi (Parma, Italy) and Microfluidics (Westwood, MA, USA). Examples of suitable equipment from these companies include the PantaPLUS 1000 and 110EH, respectively. One of these devices can be utilized to deagglomerate the particles.

[0106] Such devices involve pressurization of liquid reactant streams to pressures approaching or exceeding 2000 bar [6-8]. Pressure energy is used to drive flows through microchannels at velocities in excess of 400 m / s. These high velocities are responsible for a high degree of turbulence (corresponding to a Reynolds number of 75,000) at mixing scales of 25-50 nm. Residence times in the high energy zone of the device vary in the range of 10-90 microseconds, indicating that phenomena down to 25-50 nm have 10-90 microseconds to complete.

[0107] Once the particles are deagglomerated, the liquid stream can be mixed with another liquid stream containing the precursors of the coating. However, as mentioned above, the method of mixing these streams is important to form the actual coating. Mixing with the reactant streams can be done using a mixing device with multiple ports such as a T-mixer, a microfluidic chip, or a two-port homogenizer such as the model CR5 from Microfluidics (Westwood, MA) or MMR Technology.

[0108] The last two devices provide high shear and the ability to simultaneously pump two or more fluid streams at a given velocity. Thus, using the CR5, particle deagglomeration and mixing of reactants can occur in a single step.

[0109] One way to practice the methods of the present disclosure is to use a modified high pressure homogenizer (HPH) or microfluidizer type processor [6]. Such equipment is commonly used to deagglomerate particles suspended in liquids or to break down large solid or liquid particles to form formulations with micron- and nano-sized particles. Equipment used in these methods is commercially available from companies such as Niro Soavi (Parma, Italy), Microfluidics (Westwood, MA, USA), and DyHydromatics (Maynard, MA, USA). Examples of suitable equipment from these companies include PantaPLUS 1000, 110EH, and PSI 20, respectively. One of these devices can be utilized to deagglomerate particles.

[0110] In certain embodiments of the present disclosure, it is useful to use the above-mentioned device modified to also allow multiple streams of liquid to enter the device. Modifications can be made (for example) according to reference [7] or model CR5 or MMR technologies from Microfluidics (Westwood, MA), or by other homogenizer manufacturers.

[0111] The above method and final result differ from the Layer-by-Layer (LbL) fabrication technique described in JJ Kirkland (1965). "Porous Thin-Layer Modified Glass Bead Supports for Gas Liquid Chromatography". Analytical Chemistry. 37:1458. doi:10.1021 / ac60231a004 and also RK Her (1966). "Multilayers of Colloidal Particles". Journal of Colloid and Interface Science. 21:569. doi:10.1016 / 0095-8522(66)90018-3. That technique consists of depositing alternating layers of oppositely charged materials with washing steps in between. It is therefore only applicable to compounds that carry a charge. Below are some important differences between the LbL technique and the method of the present disclosure.

[0112] (a) LbL methods are based on oppositely charged species. In LbL methods, the charge of the particle attracts species with the opposite charge, which ultimately forms a layer. The disclosed method does not rely on the charge of the species to form a layer, so it can be used for uncharged species. In the methods described herein, the particle to be coated is in close proximity to the layered material as it is being synthesized. Thermodynamics generally favor the adsorption of the layered material on the particle, since the total surface area of ​​the particle and layered material, along with the surface energy, decreases when the layered material forms a layer around the particle rather than around other particles. This controls both the location and timing of the layer formation.

[0113] If the layers are held together only by electrostatic charges, as in the case of LbL methods, the particles may break apart when used in an environment with a different pH or ionic strength than the environment in which they were produced. This may be undesirable, as the particles may break apart prematurely before they reach their intended target. In contrast, if the layers are not held together only by charges, they are more stable in pH and ionic strength changes. The methods of the present disclosure do not rely on charged species to form layers. Therefore, they can be used on charged or uncharged materials.

[0114] (b) The LbL method does not specify deagglomeration of the core particles. Deagglomeration is advantageous because it exposes the particle surface and thus a layer forms around the particles.

[0115] The following non-limiting examples illustrate certain advantages and improvements of the methods and layered particles of the present disclosure. These examples are for illustrative purposes only and are not intended to limit or exclude other embodiments of the present disclosure.

[0116] Example 1: Calcium phosphate particles Stream 1. 5mg / ml sodium phosphate, 50ml. Flow 2. 5mg / ml calcium chloride, 40ml. Stream 1 is poured into a vessel, a HPH, model PSI-20 from DyHydromatics (Maynard, MA). Stream 2 is drawn up with a pipette. The tip of the pipette is placed at the outlet of the vessel. The pressure is set at 20,000 psi. The machine is started and after 2-3 seconds the pipette handle is depressed, thereby dispensing a small amount of stream 2 during the compression stroke of the machine. After dispensing 20 ml of stream 2 in 1 minute, a 1 ml sample is taken and the particle size is measured. The particle size analyzer used is a Litesizer 500 dynamic light scattering instrument from Anton Paar (Graz, Austria). As more of stream 2 is dispensed, totalling about 25 ml, the liquid in the vessel becomes cloudy. Another sample is obtained for particle size measurement. Dispensing stream 2 is then stopped while the machine is still running. The appearance of the liquid remains unchanged after 10-15 minutes of processing.

[0117] The particles are highly agglomerated and the agglomerates are measured in the micron size range as shown below. 2.288 microns (2288 nm) - after addition of 20 ml of stream 2 4.666 microns (4666 nm) - After all additions of 40 ml of stream 2

[0118] The primary particle size is less than 200 nm.

[0119] Example 2. Calcium phosphate / RNA particles Flow 1. 5mg / ml sodium phosphate-2.5mg / ml RNA solution, 50ml Stream 2. 5mg / ml calcium chloride solution, 40ml In Example 2, the same equipment as in Example 1 is used.

[0120] Stream 1 is poured into the machine vessel. Stream 2 is drawn up with a pipette. The tip of the pipette is placed at the outlet of the vessel. The pressure is set to 20,000 psi. The machine is started and after 2-3 seconds the pipette handle is depressed, thereby dispensing a small amount of stream 2 during the compression stroke of the machine. After dispensing 20 ml of stream 2 in about 1 minute a sample (1 ml) is taken and particle size is measured. As more is dispensed from stream 2, the liquid in the vessel becomes cloudy. Another 1 ml sample is obtained for particle size measurement. Dispensing stream 2 is then stopped while the machine is still running. After 2-3 minutes the sample becomes clear.

[0121] As can be seen below, the primary particle size is easily determined because the particles are stable (not agglomerated) for more than one hour after production. After addition of 134 nm - 20 ml of flow 2 After all additions of 207nm-40ml of flow 2

[0122] Example 3. Calcium phosphate / RNA particles This example is similar to Example 2, but with double the concentrations of sodium phosphate, RNA, and calcium chloride.

[0123] Flow 1. 10mg / ml sodium phosphate-5mg / ml RNA solution, 50ml Stream 2. 10mg / ml calcium chloride solution, 40ml The same equipment was used here as in Example 1.

[0124] Stream 1 is poured into the machine vessel. Stream 2 is drawn up with a pipette. The tip of the pipette is placed at the outlet of the vessel. The pressure is set to 20,000 psi. The machine starts and after a few seconds the pipette handle is pressed down, thereby dispensing a small amount of stream 2 during the compression stroke of the machine. After dispensing 20 ml of stream 2 in 1 minute, a sample is taken and particle size is measured. As more from stream 2 is dispensed at the same rate as before, the liquid in the vessel becomes cloudy. Another 1 ml sample is obtained for particle size measurement. Dispensing stream 2 is then stopped while the machine is still running. After 2-3 minutes the sample has become more transparent.

[0125] As can be seen below, the primary particle size is easily determined because the particles are stable (not agglomerated) for more than one hour after production. After addition of 184 nm - 20 ml of flow 2 After all additions of 1100nm-40ml flow 2 The primary particle size is less than 200 nm.

[0126] Example 4 Calcium phosphate / RNA particles This example is similar to Example 2, but the volume of Stream 2 is larger.

[0127] Flow 1. 10mg / ml sodium phosphate-5mg / ml RNA solution, 50ml Stream 2. 10mg / ml calcium chloride solution, 60ml The same equipment used in Example 1 was used in this example.

[0128] Stream 1 is poured into the machine vessel. Stream 2 is drawn up with a pipette. The tip of the pipette is positioned at the outlet of the vessel. The pressure is set at 20,000 psi. The machine is started and after a few seconds the pipette handle is depressed, thereby dispensing a small amount of stream 2 during the compression stroke of the machine. After dispensing 20 ml of stream 2 within 45 seconds, a 1 ml sample is taken and measured for particle size. As more from stream 2 is dispensed at the same rate as before, the liquid in the vessel becomes cloudy.

[0129] Another 1 ml sample is taken for particle size measurement. Dispensing stream 2 is then stopped while the machine is still running. After 2-3 minutes the sample becomes more transparent.

[0130] As can be seen below, the primary particle size is easily determined because the particles are stable (not agglomerated) for more than one hour after production. After addition of 134nm-30ml of flow 2 After all additions of 380nm-40ml flow 2

[0131] The primary particle size is 70-150 nm.

[0132] After preparation, the suspension is passed through a 0.22 micron filter to determine if there is a need to filter or sterilize the particles, which is necessary for the formulation to be injected into the human or non-human animal body.

[0133] References JPEG0007637962000002.jpg188153 Each of the above references is incorporated herein by reference in its entirety.

[0134] Although embodiments have been disclosed, the present invention is not limited to the disclosed embodiments. Instead, this application is intended to cover any variations, uses, or adaptations of the present invention using its general principles. Moreover, this application is intended to cover departures from the present disclosure as come within known or customary practice in the art to which the present invention pertains and which fall within the limits of the appended claims.

Claims

1. 1. A method for producing layered particles, comprising the steps of: (a) forming a first liquid stream comprising: (i) introducing one or more core particles into a first liquid carrier; (ii) mixing the one or more core particles in the first liquid carrier to form a first mixture; (iii) optionally homogenizing the first mixture; and (iv) introducing into the first mixture one or more reactants selected from the group consisting of an acid, a base, a polymer, a solvent, and a salt; (b) forming a second liquid stream comprising: (i) introducing into a second liquid carrier one or more reactants selected from the group consisting of an acid, a base, a polymer, a solvent, and a salt; (ii) mixing the one or more reactants in a second liquid carrier to form a second mixture; and (iii) optionally homogenizing the second mixture; (c) continuously feeding said first liquid stream into a first port of a multi-port mixer; (d) continuously feeding said second liquid stream into a second port of said multi-port mixer; and (e) mixing said first liquid stream and said second liquid stream in said mixing device for an effective period of time to form a layer on said one or more core particles. Equipped with said effective mixing having an average energy ratio of about 10 per kilogram of liquid stream mixture; ５ ~about 10 １０ In the mixing device, and, when the first and second liquid streams are mixed in step (e), the one or more reactants in the first liquid stream react with the one or more reactants in the second liquid stream; or the one or more reactants in the first liquid stream and the one or more reactants in the second liquid stream comprise a dissolved salt, which precipitates when the dissolved salt in the first liquid stream and the dissolved salt in the second liquid stream come into contact during the mixing step (e); It is a method, The method of any one of claims 1 to 5, wherein the one or more core particles comprise one or more of the following or derivatives thereof: a) Polymers: poly(lactic acid) (PLA), poly(lactide-co-glycolide) (PLGA), poly(ε-caprolactone) (PCL), starch, polysaccharides, biocompatible polymers, poly(acrylates), and poly(styrene), cross-linked polymers, alginates, polymers including PES (PEGylated polymers), and their derivatives; b) Lipids: cholesterol, phospholipids, lecithin, soy lecithin, egg lecithin, cationic lipids, neutral lipids, and sterols and their derivatives. In some embodiments, the one or more liquids are selected from lipids containing poly(ethylene glycol) (PEGylated), fluorescent lipids, and cross-linked lipids; c) gelatin, sucrose, dextrose, RNA, DNA, nucleic acid containing species, peptides, proteins, monoclonal antibodies, small molecule drugs, curcumin, plant sterols, carotenoids, and vitamin C; d) vegetable oils, soybean oil, olive oil, canola oil, corn oil, palm oil, sesame oil, vitamin E, nut oils, fish oils, omega-3 containing oils, monoglycerides, oligoglycerides, polyglycerides, vitamin A, vitamin K, oleic acid, mineral oil, squalene, squalene, essential oils, waxes, perfluorocarbons, perfluorodecalene, and FC-43; e) sodium chloride, sodium carbonate, sodium phosphate, sodium salts, calcium carbonate, calcium phosphate, calcium salts, magnesium phosphate, aluminosilicates, silica, alumina, zirconia, metal oxides, barium titanate, PZT (lead zirconate titanate), carbon, graphite, glassy carbon, amorphous carbon, gold, silver, platinum, palladium, metal particles, and derivatives thereof; f) anti-cancer drugs, antibiotics, anesthetics, anti-inflammatory drugs, ophthalmic drugs, vaccines, adjuvants, and painkillers; and g) Polysorbates, Tween 80, Tween 20, Tween 60, polyoxyethylene octylphenyl ether, Triton-X100, Igepal CA-630, various Kolliphor™ materials, Soluplus®, Collidon®, Span® 85, sorbitan trioleate, albumin, whey protein, xanthan gum, and derivatives thereof.

2. Step (a)(iv) further comprises introducing one or more surfactants into the first mixture. The method of claim 1.

3. prior to step (a)(i), further comprising washing the one or more core particles, or further comprising suspending the one or more core particles in a solution; The method of claim 1.

4. the effective period being from about 1 microsecond to about 1 hour; The method of claim 1.

5. and step (e) further comprises washing the one or more layered particles. The method of claim 1.

6. the one or more reactants in the first liquid stream are acids and the one or more reactants in the second liquid stream are bases, and the acid and the base react to form a salt; or the one or more reactants in the first liquid stream are bases and the one or more reactants in the second liquid stream are acids, and the acids and bases react to form salts. The method of claim 1.

7. The same liquid carrier is used in the first liquid stream and the second liquid stream. The method of claim 1.

8. the layered particles comprise crystalline solid particles; The method of claim 1.

9. One or more active ingredients are encapsulated in the layered particles. The method of claim 1.

10. the salts in the first liquid stream comprise calcium chloride or other calcium salts and the salts in the second liquid stream comprise sodium phosphate or other phosphate salts; or the salt in the first liquid stream comprises sodium phosphate and the salt in the second liquid stream comprises calcium chloride; or the salt in the first liquid stream comprises calcium chloride and the salt in the second liquid stream comprises sodium carbonate; The method of claim 1.

11. the core particles in the first liquid stream comprise nucleic acid; The method of claim 10.

12. 3. The method of claim 2, wherein the liquid carrier in the first liquid stream is aqueous and the liquid carrier in the second liquid stream comprises one or more water-miscible organic solvents having one or more polymers dissolved in the solvent.

13. the one or more solvents comprise a water-miscible alcohol or a water-miscible ketone; The method of claim 12.

14. 1. A method for producing layered particles, comprising the steps of: (a) forming a first liquid stream (S1) comprising: (i) introducing one or more reactants selected from the group consisting of an acid, a base, a polymer, a solvent, and a salt into a first liquid carrier (C1) to form said first liquid stream (S1); and (ii) optionally homogenizing said first liquid stream (S1); (b) forming a second liquid stream (S2) comprising: (i) introducing one or more reactants selected from the group consisting of an acid, a base, a polymer, a solvent, and a salt into a second liquid carrier (C2) to form said second liquid stream (S2); and (ii) optionally homogenizing said second liquid stream (S2); (c) feeding said first liquid stream (S1) into a first port of a multi-port mixer; (d) feeding said second liquid stream (S2) into a second port of said multi-port mixer; (e) mixing said first liquid stream (S1) with said second liquid stream (S2) to form one or more core particles, said mixing being performed at an average energy ratio of about 10 per kilogram of liquid stream mixture. ５ ~about 10 １０ A step carried out in said mixing device at W / kg; and (f) utilizing said core particles to produce layered particles, comprising: (i) forming a first liquid stream (FS1) comprising: (1) introducing said one or more core particles into a first liquid carrier (FC1); (2) mixing the one or more core particles in the first liquid carrier (FC1) to form a first mixture; (3) optionally homogenizing the first mixture; and (4) introducing into the first mixture one or more reactants selected from the group consisting of an acid, a base, a polymer, a solvent, and a salt; (ii) forming a second liquid stream (FS2) comprising: (1) introducing into a second liquid carrier (FC2) one or more reactants selected from the group consisting of an acid, a base, a polymer, a solvent, and a salt; (2) mixing the one or more reactants in the second liquid carrier (FC2) to form a second mixture; and (3) optionally homogenizing the second mixture; (iii) continuously feeding said first liquid stream (FS1) into a first port of a multi-port mixer; (iv) continuously feeding said second liquid stream (FS2) into a second port of said multi-port mixer; and (v) mixing said first liquid stream (FS1) and said second liquid stream (FS2) in said mixing device for an effective period to form a layer on said one or more core particles, said effective period mixing being at an average energy ratio of about 10 per kilogram of liquid stream mixture; ５ ~about 10 １０ A step of mixing the mixture in the mixing device at 1000 W / kg. A method comprising: when the first liquid stream (FS1) and the second liquid stream (FS2) are mixed in step (f)(v), the one or more reactants in the first liquid stream (FS1) react with the one or more reactants in the second liquid stream (FS2); or the one or more reactants in the first liquid stream (FS1) and the one or more reactants in the second liquid stream (FS2) comprise a dissolved salt, which precipitates when the dissolved salt in the first liquid stream (FS1) and the dissolved salt in the second liquid stream (FS2) come into contact during the mixing step (f)(v); and The method of claim 1, wherein the one or more core particles comprise one or more of the following or derivatives thereof: a) Polymers: poly(lactic acid) (PLA), poly(lactide-co-glycolide) (PLGA), poly(ε-caprolactone) (PCL), starch, polysaccharides, biocompatible polymers, poly(acrylates), and poly(styrene), cross-linked polymers, alginates, polymers including PES (PEGylated polymers), and their derivatives; b) Lipids: cholesterol, phospholipids, lecithin, soy lecithin, egg lecithin, cationic lipids, neutral lipids, and sterols and their derivatives. In some embodiments, the one or more liquids are selected from lipids containing poly(ethylene glycol) (PEGylated), fluorescent lipids, and cross-linked lipids; c) gelatin, sucrose, dextrose, RNA, DNA, nucleic acid containing species, peptides, proteins, monoclonal antibodies, small molecule drugs, curcumin, plant sterols, carotenoids, and vitamin C; d) vegetable oils, soybean oil, olive oil, canola oil, corn oil, palm oil, sesame oil, vitamin E, nut oils, fish oils, omega-3 containing oils, monoglycerides, oligoglycerides, polyglycerides, vitamin A, vitamin K, oleic acid, mineral oil, squalene, squalene, essential oils, waxes, perfluorocarbons, perfluorodecalene, and FC-43; e) sodium chloride, sodium carbonate, sodium phosphate, sodium salts, calcium carbonate, calcium phosphate, calcium salts, magnesium phosphate, aluminosilicates, silica, alumina, zirconia, metal oxides, barium titanate, PZT (lead zirconate titanate), carbon, graphite, glassy carbon, amorphous carbon, gold, silver, platinum, palladium, metal particles, and derivatives thereof; f) anti-cancer drugs, antibiotics, anesthetics, anti-inflammatory drugs, ophthalmic drugs, vaccines, adjuvants, and painkillers; and g) Polysorbates, Tween 80, Tween 20, Tween 60, polyoxyethylene octylphenyl ether, Triton-X100, Igepal CA-630, various Kolliphor™ materials, Soluplus®, Collidon®, Span® 85, sorbitan trioleate, albumin, whey protein, xanthan gum, and derivatives thereof.

15. the first mixture is selected from a suspension and an emulsion; or the second mixture is selected from a suspension, a solution, and an emulsion; The method of claim 1.

16. the one or more core particles are present in the liquid stream mixture of step (e) in an amount of about 0.01% to about 50% (weight of the one or more core particles / (weight of the liquid stream mixture of step (e) plus the one or more core particles)); The method of claim 1.

17. The homogenization of step 1(a)(iii) and step 1(b)(iii) is carried out at a pressure of about 500 psi to 45,000 psi; The method of claim 1.

18. the mixing device further comprises a homogenizer or rotor-stator mixer having a processing module; and the residence time of the mixing device in the processing module is from about 1 microsecond to about 100 microseconds; The method of claim 1.

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