Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
  • B01J13/02—Making microcapsules or microballoons
  • B01J13/04—Making microcapsules or microballoons by physical processes, e.g. drying, spraying
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/501—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
  • B01F23/40—Mixing liquids with liquids; Emulsifying
  • B01F23/41—Emulsifying
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
  • B01F23/40—Mixing liquids with liquids; Emulsifying
  • B01F23/45—Mixing liquids with liquids; Emulsifying using flow mixing
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
  • B01F23/80—After-treatment of the mixture
  • B01F23/808—Filtering the mixture
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
  • B01J13/02—Making microcapsules or microballoons
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
  • B01J2/00—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic
  • B01J2/006—Coating of the granules without description of the process or the device by which the granules are obtained
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B32—LAYERED PRODUCTS
  • B32B—LAYERED PRODUCTS, i.e. PRODUCTS BUILT-UP OF STRATA OF FLAT OR NON-FLAT, e.g. CELLULAR OR HONEYCOMB, FORM
  • B32B5/00—Layered products characterised by the non- homogeneity or physical structure, i.e. comprising a fibrous, filamentary, particulate or foam layer; Layered products characterised by having a layer differing constitutionally or physically in different parts
  • B32B5/16—Layered products characterised by the non- homogeneity or physical structure, i.e. comprising a fibrous, filamentary, particulate or foam layer; Layered products characterised by having a layer differing constitutionally or physically in different parts characterised by features of a layer formed of particles, e.g. chips, powder or granules
• • C—CHEMISTRY; METALLURGY
  • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
  • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
  • C09B67/00—Influencing the physical, e.g. the dyeing or printing properties of dyestuffs without chemical reactions, e.g. by treating with solvents grinding or grinding assistants, coating of pigments or dyes; Process features in the making of dyestuff preparations; Dyestuff preparations of a special physical nature, e.g. tablets, films
  • C09B67/0097—Dye preparations of special physical nature; Tablets, films, extrusion, microcapsules, sheets, pads, bags with dyes
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
  • B01F23/40—Mixing liquids with liquids; Emulsifying
  • B01F23/41—Emulsifying
  • B01F23/413—Homogenising a raw emulsion or making monodisperse or fine emulsions
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F23/00—Mixing according to the phases to be mixed, e.g. dispersing or emulsifying
  • B01F23/40—Mixing liquids with liquids; Emulsifying
  • B01F23/41—Emulsifying
  • B01F23/414—Emulsifying characterised by the internal structure of the emulsion
  • B01F23/4146—Emulsions including solid particles, e.g. as solution or dispersion, i.e. molten material or material dissolved in a solvent or dispersed in a liquid
• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
  • B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
  • B01F29/00—Mixers with rotating receptacles

Definitions

• the present disclosure provides layered small particles that may have complex functionalities, along with processes for manufacturing such particles.
• Small particles have applications in many different industries, including without limitation the pharmaceutical, food, energy, and fine chemical industries. Because of their size, such particles are capable of reducing diffusion limitations, and therefore may 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 for enhancing the delivery rates of biologically active ingredients that would otherwise be difficult to deliver, including without limitation hydrophobic drugs that tend to have poor solubility in water.
• biologically active ingredients benefit from being encapsulated within small particles to protect them until they are in close proximity to their intended biological or molecular target.
• the circumstances and timing of the release of the active ingredient need to be precisely controlled.
• the active ingredient may prematurely separate from the particles and migrate to the surface before the biological target is reached. Because of this tendency, there is a need to prevent the active ingredient from early release from small particle carriers in order to retain their desired biological activity.
• RNA interference agents such as small interfering RNA (siRNA) or micro interfering RNA (miRNA) agents.
• siRNA small interfering RNA
• miRNA micro interfering RNA
• naked RNA and DNA agents can be toxic and are readily attacked by the immune system of the body. As a result, the in vivo efficacy has not lived up to expectations based on in vitro results and serious side effects have also been observed.
• RNA-based therapeutics have garnered significant attention in recent years due to their potential to treat a variety of chronic diseases such as cardiovascular, kidney, oncology, infectious, inflammatory, and metabolic diseases.
• the promise of RNA therapeutics is linked to their excellent gene silencing potential, high target specificity, and preliminary positive results seen in early stage clinical trials.
• the ease of producing such therapeutics with high purity has contributed to their widespread popularity.
• Industry Analysis and Forecast, 2014 - 2020 suggests that the RNA based therapeutics market should reach $1.2 billion by 2020, registering a compound annual growth rate of 28.4% during 2014 - 2020.
• RNA therapeutics will likely never reach their full potential unless improved delivery technology is developed.
• RNAi represents an area of RNA therapeutics that would benefit greatly from improved delivery technology. RNAi was first discovered in plants, but it was not widely noted in animals until Andrew Fire and Craig Mello demonstrated that double- stranded RNA can cause greater suppression of gene expression than single- stranded RNA in Caenorhabditis elegans [3].
• the RNAi approach utilizes short nucleotide sequences (for example, 20-30 nucleotides) that selectively bind to their target messenger RNA in the RNA- induced silencing complex (RISC) to promote their degradation, thereby mitigating the expression of the corresponding gene.
• RISC RNA- induced silencing complex
• layered particles A number of small particle-based formulations have been developed in the past, but they have suffered from various problems and as a result, have not been adopted for widespread use. Often, nano- and micron- size particles in these formulations lacked the complex functionality required to survive inhospitable environments or to perform effectively once they successfully reach their targets. To achieve the required functionality needed for optimal activity, it would be desirable to create layered particles.
• a particle having one or more layers could be utilized and each layer could provide the particle with a different functionality designed for a specific purpose.
• layered particles could provide protection for an active ingredient from oxidation, sequential delivery of multiple active ingredients from a single layered particle, modification of the surface properties of the particles to enhance biocompatibility, or provide stealthiness in a reactive biological environment.
• RNA and DNA biologically active ingredients
• cGMP current good manufacturing practices
• One process currently used to produce layered particles to deliver biologically active ingredients uses calcium phosphate.
• calcium phosphate is a desirable starting material for biologically active small particles.
• Calcium phosphate is benign and already exists in the body. Additionally, calcium phosphate is positively charged, which matches well with the negative charge of the RNA and DNA fragments.
• calcium phosphate particles have significant drawbacks.
• calcium phosphate particles (1) are notoriously unstable, (2) may not allow for complete encapsulation or full protection of the active agent, and (3) are difficult to manufacture on a large scale or under conditions appropriate for pharmaceutical manufacturing.
• formulations used by developers of these therapies use lipid particles instead, which have other well-known problems, including toxicity from cationic lipids and liver interactions.
• United States Patent No. 5,593,875 [2] describes the formation of calcium phosphate particles for transfection. These particles are formed by simply mixing dilute liquid 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 particle growth, while simultaneously cells to be transfected are added to the dilute solution.
• the particles described have several drawbacks: these particles (1) do not have layers, (2) are produced in dilute solutions, (3) have growth that cannot be easily controlled, and (4) must be used simultaneously with final dilution that stops the growth. As a result, this process, in addition to being inefficient, would not be practical for use in a clinical setting.
• the present disclosure addresses the problems described above by providing processes for the preparation of layered particles.
• Another aspect of the present disclosure provides particles prepared by the processes of the present disclosure. Other embodiments are also disclosed.
• the processes of the present disclosure allow for building one or more layers on small particles with precise dimensions. These processes can generate particles having concentrations that are higher than the concentrations using conventional processes, therefore, increasing the efficiency of the manufacturing process.
• the processes of the present disclosure avoid the use of organic solvents and can completely encapsulate the active ingredient by creating one or more layers around the particle.
• the processes of the present disclosure can create one or more layers on the surface of the particles that can modify surface and release properties of the active ingredient(s), as desired.
• the layered particles according to the present disclosure are capable of delivering precise amounts of active ingredients in a controlled and effective manner.
• Figure 1 shows a layered particle in accordance with an embodiment.
• Figure 2 shows a layered particle in accordance with an embodiment.
• Figure 3 shows a layered particle in accordance with an embodiment.
• Figure 4 shows a layered particle in accordance with an embodiment.
• Figure 5 shows a layered particle in accordance with an embodiment.
• Figure 6 shows a process of preparing layered particles in accordance with an embodiment.
• Figure 7A shows part of a process of preparing layered particles in accordance with an embodiment.
• Figure 7B shows part of a process of preparing layered particles in accordance with an embodiment.
• Figure 8A shows part of a process of preparing layered particles in accordance with an embodiment.
• Figure 8B shows part of a process of preparing layered particles in accordance with an embodiment.
• One aspect of the present disclosure provides a process for the preparation of layered particles.
• the process comprises:
• step (a)(iv) further comprises introducing one or more surfactants into the first mixture.
• step (b)(i) further comprises introducing one or more surfactants into the second liquid carrier.
• step (a) further comprises washing the one or more core particles.
• layered particles means core particles having one or more layers.
• step (b) further comprises washing the one or more core particles.
• the term "effective period of time" is that period of time that sufficiently mixes the first liquid stream and the second liquid stream to form a layer on the one or more core particles.
• the effective period of time is from about 1 microsecond to about 1 hour. In other embodiments, the effective period of time is from about 1 microsecond to about 20 seconds. In other embodiments, the effective period of time is from about 1 microsecond to about 1 minute. In other embodiments, the effective period of time is from about 1 microsecond to about 100 microseconds. In some embodiments, the effective period of time is from about 10 microseconds to about 90 microseconds.
• the process of the present disclosure further comprises suspending the one or more core particles in a solution. In some embodiments, the process of the present disclosure further comprises deagglomerating the one or more core particles. In some embodiments, the process further comprises suspending the one or more layered particles in a solution. In some embodiments, the process of the present disclosure further comprises deagglomerating the one or more layered particles. In some embodiments, step (e) further comprises washing the one or more layered particles. In some embodiments, the process of the present disclosure further comprises repeating steps (a)(iv) and (b)(iii) to step (e) to increase the thickness of the layer. In some embodiments, the process of the present disclosure further comprises repeating steps (a) to (e) to form a second layer.
• the process of the present disclosure further comprises suspending the one or more layered particles in a solution. In some embodiments, the process of the present disclosure further comprises deagglomerating the one or more layered particles. In some embodiments, the process of the present disclosure further comprises filtering the mixture to remove particles having sizes from about 200 nanometers (nm) to about 25 microns.
• the process of the present disclosure further comprises sterilizing the mixture.
• the process of the present disclosure further comprises lyophilizing the one or more layered particles. In some embodiments, the process of the present disclosure further comprises drying the one or more layered particles. In some embodiments, the process of the present disclosure further comprises heat treating the one or more layered particles.
• the one or more reactants in the first liquid stream are acids. In some embodiments, the one or more reactants in the first liquid stream are bases. In some embodiments, the one or more reactants in the second liquid stream are bases. In some embodiments, the one or more reactants in the second liquid stream are acids. In some embodiments, the acids and bases react to form a salt. In some embodiments, the reactants in the first liquid stream and the second liquid stream are salts. In some embodiments, the salts react to form another salt.
• the same liquid is used in the first liquid stream and the second liquid stream. In some embodiments, a different liquid is used in the first liquid stream and the second liquid stream.
• 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.
• the layered particles are selected from small molecules, nucleic acids, proteins, peptides, and monoclonal antibodies.
• one or more active pharmaceutical ingredients are encapsulated in the layered particles.
• one or more active pharmaceutical ingredients are embedded in matrices within the layered particles.
• the matrices are selected from polymers, metal oxides, organic salts, inorganic salts, lipids, oils, and waxes.
• the one or more core particles or one or more layers include without limitation one or more of the following or the derivatives thereof:
• Polymers poly(lactic acid) (PLA), poly(lactide-co-glycolide) (PLGA), poly(epsilon- caprolactone) (PCL), starches, polysaccharides, biocompatible polymers, poly(acrylates), and poly(styrene), crosslinked polymers, alginates, polymers containing PES (pegylated polymers), and derivatives thereof;
• PLA poly(lactic acid)
• PLGA poly(lactide-co-glycolide)
• PCL poly(epsilon- caprolactone)
• starches starches, polysaccharides, biocompatible polymers, poly(acrylates), and poly(styrene), crosslinked polymers, alginates, polymers containing PES (pegylated polymers), and derivatives thereof;
• Lipids cholesterol, phospholipids, lecithin, soybean lecithin, egg lecithin, cationic lipids, neutral lipids, and sterols, and derivatives thereof.
• the one or more liquids are selected from lipids containing poly(ethylene glycol) (pegylated), fluorescent lipids, and crosslinking lipids;
• Gelatin sucrose, dextrose, RNA, DNA, species containing nucleic acids, peptides, proteins, monoclonal antibodies, small molecule drugs, curcumin, plant sterols, carotenoids, and vitamin C;
• Vegetable oil soybean oil, olive oil, canola oil, corn oil, palm oil, sesame oil, vitamin E, nut oils, fish oil, omega-3 containing oils, monoglycerades, oligoclycerades,
• polyglycerades vitamin A, vitamin K, oleic acid, mineral oil, squalene, squalene, essential oils, waxes, perfluorocarbons, perfluodecalene, and FC-43;
• Cancer drugs antibiotics, anesthetic drugs, anti-inflammatory, ocular drugs, vaccines, adjuvants, and pain medication;
• Triton-X 100 Igepal CA-630, various KolliphorTM materials, Soluplus®, Collidon®, Span® 85, sorbitan triolate, albumin, whey protein, xanthan gum, and derivatives thereof.
• the first liquid carrier includes without limitation water, buffer solution, ethanol, methanol, acetone, dimethyl sulfoxide (DMSO), N-Methyl-2-pyrrolidone (NMP), tetrahydrofuran, acetonitrile, poly(ethylene glycol),dichloromethane, heptane and other limonene and 2-methyl tetrahydrofuran (2-MeTHF), glycerol, and derivatives and combinations thereof.
• DMSO dimethyl sulfoxide
• NMP N-Methyl-2-pyrrolidone
• tetrahydrofuran acetonitrile
• 2-MeTHF 2-methyl tetrahydrofuran
• the one or more reactants include without limitation 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.
• the second liquid carrier includes without limitation water, buffer solution, ethanol, methanol, acetone, dimethyl sulfoxide (DMSO), N-Methyl-2-pyrrolidone (NMP), tetrahydrofuran, acetonitrile, poly(ethylene glycol),dichloromethane, heptane and other limonene and 2-methyl tetrahydrofuran (2-MeTHF), glycerol, and derivatives and combinations thereof.
• DMSO dimethyl sulfoxide
• NMP N-Methyl-2-pyrrolidone
• tetrahydrofuran acetonitrile
• 2-MeTHF 2-methyl tetrahydrofuran
• 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 liquid stream and second liquid stream are mixed in step (e).
• the one or more reactants in the first liquid stream and the one or more reactants in the second liquid stream contain dissolved salts that precipitate when the salts in the first liquid stream and the salts in the second liquid stream come into contact during mixing step (e).
• the salts in the first liquid stream comprise calcium chloride or any other calcium salt and the salts in the second liquid stream comprise sodium phosphate or any other phosphate salt. In some embodiments, the salts in the first liquid stream comprise sodium phosphate and the salts in the second liquid stream comprise calcium chloride.
• first liquid stream, the second liquid stream, or both the first liquid stream and the second liquid stream further comprise nucleic acids. In some embodiments, 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.
• the first liquid carrier and the second liquid carrier are the same. In some embodiments, the energy rate of the mixing in step (e) is from about 10 to about
• the first liquid stream and the second liquid stream are miscible. In some embodiments, the first liquid stream and the second liquid stream 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.
• 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. 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 solvents.
• the one or more solvents comprise water miscible alcohols or water miscible ketones.
• the one or more solvents are selected from ethanol, methanol, acetone, dimethyl sulfoxide (DMSO), N-Methyl-2-pyrrolidone (NMP), tetrahydrofuran, acetonitrile, and poly(ethylene glycol).
• the one or more polymers are selected from poly(lactic acid) (PLA), poly(lactide-co-glycolide) (PLGA), poly(epsilon-caprolactone) (PCL), starches, polysaccharides, biocompatible polymers, poly(acrylates), and poly(styrene), and derivatives thereof.
• the one or more lipids are selected from cholesterol,
• the one or more liquids are selected from lipids containing poly( ethylene glycol) (pegylated), fluorescent lipids, and crosslinking lipids.
• 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.
• the layer results from one of precipitation, crystallization, polymerization, crosslinking, an acid-base reaction, a substitution reaction, an oxidation reaction, a reduction reaction, adsorption, and chemisorption.
• the first mixture is selected from a suspension, solution, and an emulsion.
• the second mixture is selected from a suspension, solution, and an emulsion.
• the fraction of the flow rate of the homogenizer, rotor-stator mixer or microreactor is from about 0.0001 to about 0.9. In some embodiments, the fraction is from about 0.001 to about 0.9.
• Another aspect of the present disclosure provides a process for the preparation of layered particles comprising:
• the liquid medium further comprises a surfactant.
• step (e) further comprises washing the layered particles.
• the process of the present disclosure further comprises repeating steps (a) to (e) to form a second layer.
• the same core particles, reactants, and liquid carriers are utilized. In some embodiments, different core particles, reactants, and liquid carriers are utilized.
• the process of the present disclosure further comprises suspending the layered particles in a solution. In some embodiments, the process of the present disclosure further comprises filtering the mixture to remove particles having sizes from about 200 nm to about 25 microns. In some embodiments, the process of the present disclosure further comprises sterilizing the mixture.
• the process of the present disclosure further comprises lyophilizing the layered particles. In some embodiments, the process of the present disclosure further comprises drying the layered particles. In some embodiments, the process of the present disclosure further comprises heat treating the layered particles.
• Another aspect of the present disclosure provides a process for the preparation of layered particles comprising:
• step (a)(iv) further comprises introducing one or more surfactants into the first mixture.
• step (b)(iv) further comprises introducing one or more surfactants into the second mixture.
• step (c) further comprises washing the one or more core particles.
• the process of the present disclosure further comprises repeating steps (a)(iv) and (b)(iv) to step (c) to increase the thickness of the layer.
• the process of the present disclosure further comprises repeating steps (a) to (c) to form a second layer.
• Another aspect of the present disclosure provides a process for the preparation of core particles comprising:
• the process of the present disclosure utilizes the core particles to prepare layered particles comprising the steps of:
• homogenizer for an effective period of time to form a layer on the one or more core particles.
• the process of the present disclosure further comprises washing the one or more layered particles. In some embodiments, the process of the present disclosure further comprises repeating steps (a) to (e) to form a second layer.
• Another aspect of the present disclosure provides a layered particle prepared by the processes of the present disclosure.
• Another aspect of the present disclosure provides a core particle prepared by the processes 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.
• energy levels of about 10 5 to about 10 10 W/kg are typical. In some embodiments, the energy levels are 10 to about 10 10 W/kg.
• the contact times of the two streams may vary from about 2 to about 100 microseconds to about 0.5 to about 100 seconds.
• the precise contact time will depend on a variety of factors, such as the type of homogenizer, rotor-stator mixer or microreactor used.
• US Patent No. 5,187,554 [10] supports contact times in the range of 0.5 to 20 seconds. Where a high pressure homogenizer is used, the contact times at the high energy zone tend to be similar (e.g., about 2 to about 100 microseconds).
• the layered particles that are formed by the processes of the present disclosure have various characteristics.
• the Figures show for illustrative purposes only particular characteristics of particles made in accordance with different embodiments of the processes of the present disclosure.
• FIG. 1 illustrates a layered particle 10 in accordance with an embodiment.
• Layered particle 10 includes core 14 having a coating layer 12.
• Layered particle 10 can be solid, liquid or semi- solid.
• FIG. 2 illustrates layered particle 16 in accordance with an embodiment.
• Layered particle 16 includes core 14 having a coating layer 12 and coating layer 18. Coating layer 12 is surrounding core 14 and coating layer 18 is surrounding coating layer 12.
• Layered particle 16 can be solid, liquid or semi-solid.
• Figure 3 illustrates layered particle 20 in accordance with an embodiment.
• Layered particle 20 includes core 14, coating layer 12, and matrices containing active ingredient 22 embedded or dissolved within core 14.
• FIG. 4 illustrates layered particle 24 in accordance with an embodiment.
• Layered particle 24 includes core 14, coating layer 12, and crystalline material 26.
• FIG. 5 illustrates layered particle 28 in accordance with an embodiment.
• Layered particle 28 includes core 14, coating layer 12, and polyethylene glycol 30.
• Figure 6 illustrates process 32 of preparing layered particles.
• liquid stream 34 containing core particles 106 is combined with liquid stream 36 under controlled mixing conditions 38 and controlled time 40 to produce layered particles 42.
• FIG 7A shows part of a process 44 of preparing layered particles in accordance with an embodiment.
• Step 46 includes the selection of reactants, liquid carriers and surfactants for forming the core particles.
• Step 48 involves forming two or more different reactant liquid streams.
• Step 50 includes setting up the multi-port mixer for processing the liquid streams from Step 48.
• Step 52 involves processing the liquid streams to form the 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 involves selecting the reactants for the first layer.
• Step 60 involves forming two or more different reactant liquid streams.
• Step 7B shows part of a process 44 of preparing layered particles in accordance with an embodiment.
• Step 62 involves setting up the multi- port homogenizer for processing the liquid streams.
• Step 64 involves processing the liquid streams 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 optionally repeats 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 of Steps 64-72 to remove large particles or to sterilize the suspension.
• Step 76 is an optional step of lyophilizing, drying or otherwise heat treating the particles from any one of Steps 64-72.
• FIG 8A shows part of a process 78 of preparing layered particles in accordance with an embodiment.
• Step 80 involves selection of materials such as the core particles, reactants, surfactants and liquid carriers, as further described in this disclosure.
• Step 82 involves introducing the core particles into a liquid stream.
• Step 84 involves rotor- stator or homogenizer mixing to create a coarse dispersion.
• Step 86 involves high pressure homogenization to deagglomerate the particles.
• Step 88 involves formation of two or more different reactant liquid streams.
• Step 90 involves setting up a multi-port mixer for processing the liquid streams.
• Step 92 involves processing the two or more liquid streams from Step 90 using the multi-port mixer.
• FIG 8B shows part of a process 78 of preparing layered particles in accordance with an embodiment.
• Step 94 is the optional step of isolating and washing the particles.
• Step 96 is the optional step of repeating Steps 82-94 to increase the thickness of the layer using the same material.
• Step 98 is the 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 liquid solution.
• Step 102 is an optional step of filtering the suspension from any of Steps 92 or 96-100 to remove the large particles or to sterilize the suspension.
• Step 104 is an optional step of lyophilizing, drying or otherwise heat treating the particles from any one of Steps 92-100.
• the present disclosure also provides various processes for the manufacture of layered particles.
• the processes of the present disclosure affect key parameters and sub-processes that control the formation of layered particles, including: (a) de-agglomeration of the core particles to expose the surface of the core particles, and (b) forcing the process that leads to layer formation (such as chemical reaction or precipitation) to occur on the particle surface, rather than occurring independent of the particles.
• layer formation such as chemical reaction or precipitation
• Suitable materials are selected: the core particles, the reactants that will be used to form the next particle layer and the carrier liquids in each stream.
• the core particles may be commercially available or previously made. With respect to reactants, for example, one may be an acid and another is a base and upon reaction they form a salt. The reactants may also be two salts that react via substitution reactions and result in a third salt. There are other options that do not involve chemical reactions, but physical processes, such as precipitation or crystallization.
• one stream may contain a polymer dissolved in a solvent.
• the other stream may contain a liquid that is miscible with the solvent, but it does not dissolve the polymer. When these streams combine, the solubility of the polymer is reduced. This may force the polymer to precipitate.
• the carrier liquids are selected so they are compatible and typically (but not always) miscible. These carrier liquids can be aqueous solutions with various pH, organic solvents, or a combination thereof. They optionally may contain surfactants.
• Core particles are mixed in a liquid medium. Typical concentrations of the particles in the liquid range from about 0.01 to about 10 wt%, but the particle concentrations may approach about 50%, depending on the materials involved.
• one or more surfactants are mixed in the solution.
• a rotor stator mixer is used to create a coarse dispersion.
• an IKA mixer IKA Works, Inc., 2635 Northchase Parkway SE, Wilmington, NC 28405, USA
• a simple rotating propeller that is immersed in the suspension can be used. This step may not completely de-agglomerate the liquid, but creates a suspension that can be further processed.
• the key processing parameters are the rotational speeds and the type of the processing module. Speeds in the range of 500-18,000 rpm are typical, while the processing modules are selected so they are appropriate for the processing dispersions, based on the manufacturer's suggestions.
• the coarse suspension undergoes high pressure homogenization.
• the coarse suspension is first poured into the inlet reservoir of a High Pressure Homogenizer (HPH).
• HPH High Pressure Homogenizer
• a pressure is selected to be typically in the range of about 3000 to about 30,000 psi, but it can extend from about 500 psi to about 45,000 psi or more.
• the type of the processing module of the homogenizer is selected to be suitable for processing dispersions.
• the processing module based on the type of the HPH may be, for example, homogenizing valves (APV, Niro Soavi, etc.), reaction chambers (DyHydromatics) or interaction chambers (Micro fluidics).
• the outlet temperature of the processed material is controlled by the heat exchanger that is typically positioned after the processing module.
• the material may be recirculated several times until deagglomeration is complete, which can be verified using particle size analyzers, optical microscopes, or other means known to those of ordinary
• the first steam is the suspension, in which one or more of the reactants are dissolved.
• the other steam contains the other reactant or multiple reactants dissolved in a liquid miscible to the liquid of the first stream.
• concentrations of the reactants may be pre-determined based on the reaction type, kinetics and desired thickness of the layer.
• Each liquid stream is directed in a port of a two- port mixer and is fed at a predetermined rate.
• mixers There are various mixers that may be used, depending on the application. One is described, for example, in T. Panagiotou, S. Mesite, R. Fisher and I. Gruverman, "Production of Stable Drug Nanospensions Using Microfluidics Reaction Technology".
• Microfluidics may also be used.
• Low energy microfluidics reactors such as those from Precision Nanosystems (Vancouver, BC, Canada) may also be used in some situations.
• the machine is set up. Assuming that a dual port homogenizer is used, like in step 3, the pressure, processing module and temperature are selected. Additionally, the flowrate of one of the streams is controlled using a pump. Since the total flowrate of the machine is controlled by the pressure and the processing module, the flowrate of the second stream adjusts itself, so the sum of the flowrates of the two streams is equal to the total flowrate of the machine. The ratio of the flow rates of the two streams controls the stoichiometry of the chemical reaction of physical process, and therefore control the reaction rates.
• the layers are created.
• the HPH machine is turned on and the streams are mixed and react for a predetermined period, typically around 1 second total as they pass through the processing module.
• the residence time in the high energy zone of the processing module is calculated to be around 10-25 microseconds. Because the chemical reactions/physical processes are completed within these times scales and within the microliter volume of the processing module, the particles get in close proximity with the reactants and subsequently the products of the reaction. Additionally, the processes are expedited because of their small scale (as demonstrated in previous work, see references [7] -[9], for example).
• the concentrations of the reactants, the pressure, the residence times, 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 initial size below 500 nm.
• the particles are isolated and washed. It may be necessary that the particles are washed in between creating layers, so the reactants and impurities of the previous process are removed.
• One way to wash those would be to filter the particles and then wash the particles trapped on the filter with a clean liquid solution.
• Another way would be to separate the particles using a centrifuge and then wash those with a clean solution.
• Yet another way would be to separate the impurities using hollow fiber tangential filtration. This works best for relatively high MW materials including proteins, RNA, DNA, peptides, etc.
• the thickness of the layer can be increased by repeating steps 5-8.
• steps 4-8 or 9 are repeated to create another layer of the same or different material.
• Steps 1-3 are repeated to suspend the particles from Step 8 or 9 in a final liquid solution.
• the suspension is filtered to remove large particles or to filter sterilize the suspension using known filtering methods.
• the particles are lvophilized using methods known to those of ordinary skill in the art.
• the core particles are formed using the dual feed equipment described in step 5, and also publications [6]-[9] and the previous Microfluidcs U.S. Patent No. 8,187,554. These core particles may consist of solid, liquid or semi-solid materials. The following is an example: Solid polymer particles optionally containing an active ingredient are formed via solvent- antisolvent precipitation, as described in Ref. [11]. These form the core particles, while layers are formed at a later stage. It may be possible that the function of the layers is to prevent the active ingredient from leaching out of the particle prematurely.
• the core particles are formed simultaneously with at least one of the layer(s). For example, starting on step 4, reactants are selected using both for the core particles and the first layer. If the core particles form via processes that are faster than the processes required for the first layer, then the core particles will form first and the layer material will coat the particles.
• One of the liquid streams may contain a polymer, which upon precipitation creates a coating around the droplets, forming nanocapsules.
• More than two liquid reactant streams are used in Step 4 to create the coating around the particles. This is useful when multiple processes are taking place and there is a need to keep the reactants separate.
• Figure 1 shows a core spherical particle surrounded by a single layer.
• the core particle may be solid, liquid or semi-liquid.
• Solid spherical core particles, made out of polymer may be produced via micro- or nano- precipitation of the polymer in liquid, see reference [11]. They may also be produced as a result of emulsion polymerization or spray drying, see for example U.S. Patent No. 5,269,980.
• the layers may function as a barrier to prevent certain components of the particle from releasing from the particles, or slowing their release rate.
• a layer with specific electrical or electronic properties As an example, PZT (Lead Zirconium Titanate) is a piezoelectric material that is used in ultrasonic transducers and piezoelectric resonators. For such applications, it may be desirable to utilize particles coated with a PZT layer.
• the following reference describes the wet chemistry and steps to manufacture PZT.
• Liquid particles may form during emulsification. Solid layers around these particles may protect the components of the liquid particle from oxidation, reduce odor, or prevent components from leaching out. Similarly, layers around semi-liquid particles which often include lipids may protect compounds inside the particles.
• Figure 2 shows a particle with multiple layers. It is possible that each layer has a different function.
• the first layer may be used to protect certain compounds inside the core particle.
• the second layer may be used to create a surface with high biocompatibility, so the particle is accepted and not attached by the immune system.
• the core particle of Figure 3 consists of a matrix with one or more materials embedded or dissolved in.
• Example would be polymer particles with active ingredients dissolved or embedded in, as mentioned in previous paragraphs.
• Another example would be a salt, such as calcium phosphate containing RNA, DNA or peptide, molecules.
• Other examples may include sodium carbonate particles containing protein molecules.
• Figure 4 shows a core particle that is made of a crystalline material and is typically not round in shape.
• examples of such materials include solid, small molecule drugs, such as paclitaxel used for treating cancer.
• Figure 5 shows a layered particle with PEGylated species surrounding the particle. Such species are used to stabilize the particles and form a stealthy surface, so the particles for pharmaceutical applications are not detected by the immune system of the body.
• a common way to de-agglomerate particles is to suspend them in various liquids, optionally add surfactants, and then use high energy equipment to apply shear forces on the particles.
• the shear forces help separate the particles from each other, while the presence of surfactants helps keep the particles apart for a long time. The smaller the particles, the higher the required shear forces, as shown later in this section.
• There are commonly used technologies that deagglomerate the particles including High Pressure Homogenizers (HPH) and sonicators. Once the particles are deagglomerated, they are ready to get coated. One or more of the reactants that form the coating is mixed in with the particle suspension. This forms the first liquid stream. Another liquid stream is then formed.
• HPH High Pressure Homogenizers
• the second liquid stream contains reactant(s) that react with the reactant(s) in the first liquid stream.
• the reactants may undergo a chemical reaction and form another species.
• one may be an acid and another a base and upon reaction they may form a salt.
• the reactants may also be two salts that react via substitution reactions and result in a third salt.
• one stream may contain a polymer dissolved in a solvent.
• the other stream may contain a liquid that is miscible with the solvent, but it does not dissolve the polymer. When these streams get together, the solubility of the polymer is reduced. This may force the polymer to precipitate.
• the polymer may not precipitate on the particles or coat each particle with a thin layer, unless the chemical reaction or the physical process take place under controlled conditions and precise timing. This may be achieved by using the appropriate equipment that allows for the two streams to mix at the high energy, which is required for forming thin layers around the particles. Additionally, the mixing time will have to match time scale of the chemical reaction or physical process.
• Nano- and micron- size particles have high surface energies and tend to agglomerate or aggregate, which is generally accomplished by utilizing surfactants and dispersing the core particles in liquid applying shear.
• the level of shear (energy) required also depends on the type and amount of surfactant.
• the shear may be generated as a result of the kinetic energy of the liquid, as the liquid flows through pipes, orifices, channels, etc.
• the liquid is pressurized (potential energy) and as the liquid flows the potential energy is converted to kinetic energy.
• sonication can be used as an energy source.
• shear is generated as a result of tiny bubbles moving at high velocities and bursting inside the liquid.
• the reactants need to react at the surface of the core particles; or the reactants react in the liquid but precipitate on the surface of the core particles. If none of these scenarios apply, the reaction products will form particles in an independent fashion of the core particles.
• one of the reactants may be part of the surface of the core particle.
• the surface may catalyze the reaction. If the reaction occurs in the liquid phase, the products would have to coat the surface very quickly after they form, before the products grow into large independent particles. It is therefore essential that the reactants mix at a scale smaller than the core particles, so that the reactants react to form small structures, which eventually form the coating. The timing of the mixing of the reactants in relation to the reaction rate is also important.
• v is the kinematic viscosity and ⁇ is the rate of energy dissipation per unit mass in turbulent mixing.
• This Kolmogorov length, ⁇ is the length scale that is associated with the size of the smallest eddies formed prior to the dissipation of heat, and associated with the size of the entities being formed; and it also has a significant impact on the time scale for the transport processes involved. This formula shows that the smaller the particles, the larger the energy requirement is.
• a common method to deagglomerate the particles suspended in liquid is using High Pressure Homogenization (HPH) or microfluidization methods.
• HPH High Pressure Homogenization
• Equipment used for these methods is commercially available from companies such as Niro Soavi, Parma, Italy and Microfluidics, Westwood, MA, USA. Examples of pertinent equipment from these companies include PantaPLUS 1000 and 110EH, respectively. One of these pieces of equipment can be utilized to de- agglomerate the particles.
• Such equipment involves the pressurization of liquid reactant streams to pressures approaching or exceeding 2000 bars [6-8].
• the pressure energy is used to pump the streams through microchannels at velocities over 400 m/s. These high velocities, are responsible for highly turbulent flows, (corresponding to Reynolds numbers of 75,000) with mixing scales of 25-50 nm.
• the residence times in the high energy zone of the instrument vary in the range of 10- 90 microseconds indicating that phenomena down to 25-50 nm have 10-90 microseconds to complete.
• the liquid stream may be combined with another liquid stream that contains precursors of the coating.
• the mixing method of these streams is important in order to form the actual coating.
• the mixing with the reactant stream can be done using a mixing device with multiple ports, such as a T-mixer, a microfluidics chip, or a two port homogenization device, such as model CR5 or MMR technology from Microfluidics, Westwood, MA.
• the last two devices provide high shear, and in addition the ability to pump two or more fluid stream simultaneously at predetermined rates. Therefore, using the CR5, the particle deagglomeration and the mixing of the reactants may happen in one step.
• HPH High Pressure Homogenizer
• Microfluidizer-type processor [6].
• HPH High Pressure Homogenizer
• Such devices are commonly used to deagglomerate particles suspended in liquid, or to break up large solid or liquid particles, forming formulations with micron- and nano-sized particles.
• Equipment used for these methods is commercially available from companies such as Niro Soavi, Parma, Italy, Microfluidics, Westwood, MA, USA and DyHydromatics, Maynard, MA, USA. Examples of pertinent equipment from these companies include PantaPLUS 1000, 110EH and PSI 20 respectively. One of these pieces of equipment can be utilized to de-agglomerate the particles.
• the device mentioned above was modified to also allow for multiple streams of liquids to enter the device.
• the modification may be done (for example) according to reference [7], or model CR5 or MMR technology from Microfluidics, Westwood, MA, or other homogenizer manufacturer.
• the LbL method is based on oppositely charged species.
• the charges of the particles attract species with opposite charges, which eventually form a layer.
• the processes of the present disclosure do not depend on the charges of the species to form a layer, so it can be used for species that are not charged.
• the particles to be coated are brought in close proximity with the layering material, as it is being synthesized. Thermodynamics generally favors the adsorption of the layering material onto the particle because the total surface area of the particle and the layering material, along with the surface energy decreases when the layering material forms a layer around the particle, rather than a separate particle. This controls both the location and timing of the layer formation.
• the particle When the layers are held together with electrostatic charges only, as is the case of the LbL method, the particle may fall apart when it is used in an environment that has different pH or ionic strength that the environment it was produced. This may be undesirable, because the particle may fall apart prematurely, before it reaches its intended target. In contrast, when layers are not kept together with electric charges only, they are more stable in pH and ionic strength variations.
• the processes of the present disclosure do not rely on charged species to form a layer. Therefore, they can be used for materials with or without charge.
• the LbL method does not specify deagglomeration of the core particles. Deagglomeration is advantageous because it exposes the particle surfaces, so the layers form around the particles.
• Stream 1 is poured into the reservoir of a HPH, Model PSI- 20 from DyHydromatics, Maynard, MA.
• Stream 2 is siphoned with a pipette. The tip of the pipette is positioned at the outlet of the reservoir. The pressure is set at 20,000 psi. The machine starts and after two to three seconds the pipette handle is depressed such that it dispenses a small amount of Stream 2 during the compression stroke of the machine. After dispensing 20 ml of Stream 2 in 1 min, a sample of 1 ml 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 from Stream 2 is dispensed, around 25 ml total, the liquid in the reservoir becomes cloudy. Another sample is obtained for particle size measurements. Dispensing Stream 2 is then stopped while the machine is still working. The liquid does not change in appearance after processing for 10-15 minutes longer.
• the particles are highly agglomerated and the agglomerates measure in the micron size range as shown below:
• the primary particle size is less than 200 nm.
• Example 2 The same equipment as was used in Example 1 is also used in Example 2.
• Stream 1 is poured into the machine reservoir.
• Stream 2 is siphoned with a pipette.
• the tip of the pipette is positioned at the outlet of the reservoir.
• the pressure is set at 20,000 psi.
• the machine starts and after two to three seconds the pipette handle is depressed such that it dispenses a small amount of Stream 2 during the compression stroke of the machine.
• a sample (1 ml) is taken and the particle size is measured. As more from Stream 2 is dispensed, the liquid in the reservoir becomes cloudy. Another 1 ml sample is obtained for particle size measurements.
• Dispensing Stream 2 is then stopped, while the machine is still working. After 2-3 minutes, the sample becomes clear.
• the primary particle size is measured readily since the particles are stable (and not agglomerated) for over 1 hr after production, as seen below:
• This example is similar to Example 2, but with twice the concentrations of the sodium phosphate, RNA and calcium chloride.
• Stream 1 is poured into the machine reservoir.
• Stream 2 is siphoned with a pipette.
• the tip of the pipette is positioned at the outlet of the reservoir.
• the pressure is set at 20,000 psi.
• the machine starts and after a few seconds the pipette handle is depressed, so it dispenses a small amount of Stream 2 during the compression stroke of the machine.
• a sample is taken and the particle size is measured. As more from Stream 2 is dispensed at the same rate as before, the liquid in the reservoir becomes cloudy. Another 1 ml sample is obtained for particle size measurements.
• Dispensing Stream 2 is then stopped, while the machine is still working. After 2 -3 minutes, the sample became clearer.
• the primary particle size is measured readily since the particles are stable (and not agglomerated) for over 1 hr after production, as seen below:
• the primary particle size is less than 200 nm.
• This example is similar to Example 2, but with larger volume of Stream 2.
• Stream 1 is poured into the machine reservoir.
• Stream 2 is siphoned with a pipette.
• the tip of the pipette is positioned at the outlet of the reservoir.
• the pressure is set at 20,000 psi.
• the machine starts and after a few seconds the pipette handle is depressed, so it dispenses a small amount of Stream 2 during the compression stroke of the machine.
• an 1 ml sample is taken and the particle size is measured. As more from Stream 2 is dispensed at the same rate as before, the liquid in the reservoir becomes cloudy. Another sample 1 ml sample is obtained for particle size measurements.
• Dispensing Stream 2 is then stopped, while the machine is still working. After 2-3 minutes, the sample becomes clearer.
• the primary particle size is measured readily since the particles are stable (and not agglomerated) for over 1 hr after production, as seen below: 134 nm - after addition of 30 ml of Stream 2 380 nm - after addition of all 40 ml of Stream 2
• the primary particle size is 70- 150 nm.
• the suspension is passed through a 0.22 micron filter to determine if the particles need to be filtered or sterilized, which is essential for injecting the formulation in the body of a human or non-human animal.

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