HK1188175B - Apparatus and method for preparing an emulsion - Google Patents

Description

Apparatus and method for preparing an emulsion

Cross reference to related applications

This patent application claims priority to U.S. provisional application No.61/426,705 entitled "apparatus and method for preparing an emulsion" and filed on 12/23/2010, which is incorporated herein by reference in its entirety.

Technical Field

The present invention relates to an apparatus for preparing an emulsion, a method of using such an apparatus and a composition made by the method of the invention. More specifically, the disclosed apparatus is a column having dividers for dividing the packing material and directing the flow of fluid through the column to produce an emulsion product.

Background

Encapsulation of the drug in the biocompatible, biodegradable polymeric microparticles can prolong maintenance of therapeutic drug levels associated with administration of the drug itself. Depending on the formulation and the encapsulated active molecule, sustained release can extend up to several months. To prolong the presence at the target site, the drug may be formulated in a matrix as a slow release formulation. Following administration, the drug is then released by diffusion out of the matrix, or by erosion of the matrix. Encapsulation in biocompatible, biodegradable polyesters, such as, for example, copolymers of lactide and glycolide, has been used to deliver small molecule therapies ranging from insoluble steroids to small peptides. Currently, there are over tens of lactide/glycolide polymer formulations on the market, most of these formulations being in particulate form.

In addition, U.S. patent No.6,706,289, hereby incorporated by reference in its entirety, discloses controlled release formulations of bioactive molecules coupled to hydrophilic polymers, such as polyethylene glycol, and methods for their production. The formulations are based on solid microparticles formed from a combination of biodegradable polymers, such as poly (lactic acid) (PLA), poly (glycolic acid) (PGA), and copolymers thereof.

Several techniques have been reported for the production of microparticles containing biological or chemical agents by emulsion-based manufacturing techniques. In general, the method has a first phase that includes an organic solvent, a polymer, and a biological or chemical agent dissolved or dispersed in the first solvent. The second phase comprises water and a stabilizer and optionally a first solvent. The first and second phases are emulsified and, after the emulsion is formed, the first solvent is removed from the emulsion to produce hardened microparticles.

In one technique, two immiscible solutions are added to a packed bed of spherical beads within an emulsion cartridge. Ideally, the two solutions have a combined mass flow rate that forms a laminar state. The flow of solutions is repeatedly divided and recombined to form uniform fluid volumes that contain a portion of each immiscible solution. The smaller part is separated into spherical droplets as the dispersed phase in the larger part (continuous phase). The repeated division and recombination is critical for the formation of a homogenized product.

Since the above technique is scalable to larger scales, there is an increase in the parameters of the potential path length that must be traveled by each fluid element. These increases in path length result in increased residence time of the fluid elements in the packed bed emulsion column. The increase in residence time in turn affects the physical properties of the final emulsified product.

Another problem that arises during the scaling up of packed bed emulsion columns is the formation of preferred channels for fluid travel within the packed bed. The formation of the preferred channels results in "virtual cylinders" through which the flow rate increases relative to the average flow rate, and "quiescent zones" where the flow rate decreases relative to the average flow rate. The presence of these "virtual cylinders" and "quiescent zones" affects the number of homogenization events and other parameters of emulsion formation.

Thus, there is a need for an easily proportioned apparatus and method for forming emulsion-based microparticles that provide a narrow, repeatable particle size distribution that can be used in both large and small volumes. More specifically, there is a need in the related art for a column configured to maintain a consistent path length during scale-up of an emulsification process and prevent the formation of preferred channels in a packed bed.

Disclosure of Invention

Disclosed herein are columns for receiving packing material that permits fluid flow through the column. The cartridge has a periphery defining an interior cavity in fluid communication with the inlet and outlet of the cartridge. In one aspect, the inlet of the cartridge receives at least one fluid. In another aspect, the column includes at least one divider positioned within the interior cavity. In a further aspect, each divider extends along at least a portion of the longitudinal length of the interior cavity of the column. In a further aspect, the divider is configured to divide the packing material and direct fluid flow through the column. Also described are methods of making emulsions, which methods employ the disclosed cartridge.

Additional advantages will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the aspects described below. The advantages described below will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive.

Drawings

The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several aspects described below.

FIG. 1A is a perspective view of a column having an internal cavity, a longitudinal axis, and an inlet and an outlet, as described herein. FIG. 1B is a top view of the column of FIG. 1A.

Fig. 2A is a perspective view of an exemplary column having dividers, as described herein. Fig. 2B is a top view into the internal cavity of the cartridge of fig. 2A. Fig. 2C is a close-up partial cut-away view of the divider of fig. 2A.

Fig. 3A is a perspective view of an exemplary column having dividers, as described herein. Fig. 3B is a top view into the internal cavity of the cartridge of fig. 3A.

Fig. 4A is a perspective view of an exemplary column having dividers, as described herein. Fig. 4B is a top view into the internal cavity of the cartridge of fig. 4A.

Fig. 5A is a perspective view of an exemplary column having dividers, as described herein. Fig. 5B is a top view into the internal cavity of the cartridge of fig. 5A.

FIG. 6 is a schematic view of an exemplary packed bed apparatus described herein.

Detailed Description

The present invention may be understood more readily by reference to the following detailed description, examples and claims and their previous and following description. However, before the present compositions, articles, devices, and/or methods are disclosed and described, it is to be understood that this invention is not limited to the specific compositions, articles, systems, and/or methods disclosed unless otherwise specified, as such compositions, articles, systems, and/or methods can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting.

The following description of the invention is provided to enable practice of the teachings of the invention in its presently known embodiments. To this end, those skilled in the relevant art will recognize and appreciate that many changes can be made to the various aspects of the invention described herein, while still obtaining the beneficial results of the present invention. It will also be apparent that some of the desired benefits of the present invention can be obtained by selecting some of the features of the present invention without utilizing other features. Accordingly, those who work in the art will recognize that many modifications and adaptations to the present invention are possible and can even be desirable in certain circumstances and are a part of the present invention. Thus, the following description is made for the purpose of illustrating the principles of the present invention and is not meant to be limiting.

Before the present particulates, copolymers, polymer blends, compounds, ingredients, and/or methods are disclosed and described, it is to be understood that the aspects described herein are not limited to specific compounds, synthetic methods, or uses, as such specific compounds, synthetic methods, or uses may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular aspects only and is not intended to be limiting unless specifically defined herein.

In this specification and in the claims which follow, reference will be made to a number of terms which shall be defined to have the following meanings:

throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

It must be noted that, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to a "pharmaceutical carrier" includes mixtures of two or more such carriers, and the like.

"selective" or "selectively" means: the events or conditions described hereinafter may or may not occur; and the description includes instances where the event or circumstance occurs and instances where it does not.

Ranges may be expressed herein as from "about" one particular value, and/or to "about" another particular value. When such a range is expressed, another aspect includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another aspect. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint.

The term "biodegradable" refers to a polymer that dissolves or degrades in vivo within a period of time acceptable for a particular therapeutic situation. This time is typically less than five years, and is typically less than one year after exposure to physiological pH and temperature, such as a pH ranging from about 6 to about 9 and a temperature ranging from about 25 ℃ to about 38 ℃.

The term "packed bed device" refers to any reservoir containing a packing material capable of forming an emulsion upon contact with two immiscible fluids.

The term "active agent" refers to any biological or chemical agent.

The term "microparticle" refers to a particle having a diameter typically less than 1.0mm, and more typically between 1.0 and 250 μm (micrometers). Microparticles of the present invention include, but are not limited to, microspheres, microcapsules, microsponges, microparticles, and granules generally having an internal structure comprising a matrix of agents and excipients. The microparticles may also include nanoparticles.

The term "nanoparticle" refers to a particle having a diameter typically between about 20 nanometers (nm) and about 2.0 microns, more typically between about 100nm and about 1.0 micron.

"injection" is intended for parenteral preparation. Injections include, but are not limited to, liquid preparations of the drug substance or solutions or suspensions thereof.

The term "controlled release" refers to the control of the rate and/or amount of bioactive molecules delivered according to the drug delivery formulations of the present invention. The controlled release kinetics can be continuous, intermittent, variable, linear, or nonlinear. This may be accomplished using one or more types of polymer components, drug loadings, inclusion of excipients or degradation enhancers, or other modulators that are administered separately, in combination, or sequentially to produce the desired effect. "controlled release" microparticles include, but are not limited to, "sustained release" microparticles and "delayed release" microparticles.

The term "sustained release" refers to the stable release of a bioactive agent into the body over an extended period of time. The sustained release formulation provides the following capabilities: the bioactive agent is provided to the subject over a longer period of time than is achieved by typical bolus administration of the bioactive agent. Sustained release microparticles may conveniently reduce the frequency of administration of the bioactive agent.

The terms "bioactive agent", "bioactive agent" or "bioactive molecule" can be any substance that can affect any physical or biochemical property of a biological organism, including but not limited to viruses, bacteria, fungi, plants, animals, and humans. Bioactive molecules can include any substance intended for diagnosis, therapeutic alleviation, treatment, or prevention of a disease in a human or other animal, or otherwise enhancing the physical or mental well-being of a human or animal.

"treatment" refers to the medical management of a patient with the following intent: will result in the cure, alleviation, stasis or prevention of the disease, pathological condition, or disorder. This term includes active treatment, that is, treatment aimed specifically at improvement of a disease, pathological state, or disorder, and also includes causal treatment, that is, treatment aimed at removal of the cause of the disease, pathological state, or disorder. In addition, this term includes: palliative therapy, that is, therapy designed for the relief of symptoms rather than the cure of a disease, pathological condition, or disorder; prophylactic treatment, that is, treatment aimed at the prevention of a disease, pathological condition, or disorder; and supportive treatment, that is, treatment to supplement another specific therapy, with the goal of disease, pathological condition, or disorder amelioration. The term "treatment" also includes symptomatic treatment, that is, treatment directed to the constituent symptoms of a disease, pathological condition, or disorder.

The term "injectability" refers to the aspiration and delivery of microparticles through a needle without clumping of particles or clogging of the needle.

"subject" is used herein to refer to any target of administration. The subject may be a vertebrate, such as a mammal. Thus, the subject may be a human. The term does not indicate a particular age or gender. Thus, it is intended to cover adult and newborn subjects, as well as fetuses, whether male or female. "patient" refers to a subject having a disease or disorder, and includes both human and veterinary subjects.

Disclosed are compounds, ingredients, and components that can be used in, can be used in conjunction with, and/or can be used in preparation for the disclosed devices and methods. These and other materials are disclosed herein, and it is understood that when combinations, sub-groups, interactions, groups, etc. of these materials are disclosed that while specific reference of each various individual and collective combinations and permutation of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a variety of different polymers and agents are disclosed and discussed, each and every combination and permutation of the polymers and agents are specifically contemplated unless specifically indicated to the contrary. Thus, if molecular categories A, B and C and molecular categories D, E and F are disclosed, and examples of combination molecules A-D are disclosed, then even if each is not individually recited, each is individually and collectively contemplated. Thus, in this example, each of the combinations A-E, A-F, B-D, B-E, B-F, C-D, C-E and C-F are specifically contemplated and should be considered to be comprised of A, B and C; D. e and F; and disclosure of an exemplary combination a-D. Likewise, any subset and combination of these is also specifically contemplated and disclosed. Thus, for example, the subgroups of A-E, B-F and C-E are specifically contemplated and should be considered to be defined by A, B and C; D. e and F; and disclosure of an exemplary combination a-D. This concept applies to all aspects of this disclosure including, but not limited to, steps in methods of making and using the disclosed compositions. Thus, if there are a variety of additional steps that can be performed it is understood that each of these additional steps can be performed with respect to any specific embodiment or combination of embodiments of the disclosed methods, and that each such combination is specifically contemplated and should be considered disclosed.

In one broad aspect of the present invention, and referring to fig. 1A and 1B, a column 10 for receiving packing material 40 is disclosed. In one aspect, the column 10 can have a longitudinal axis 12 and a periphery 14, the periphery 14 defining an interior cavity 16. In this aspect, the interior cavity 16 may have a longitudinal length 13. It is contemplated that the packing material 40 may be configured to permit fluid flow through the column 10 along the longitudinal axis 12. It is also contemplated that the gaps formed within the filler material 40 inside the internal cavity 16 may function as channels that repeatedly span the path as the fluid flows through the column 10.

In one aspect, it is contemplated that the cartridge 10 can be a reservoir of any shape that can be filled with the filler material 40. For example, it is contemplated that the cross-section of the column 10 may be generally rectangular, square, round, or circular. In an exemplary aspect, as shown in fig. 1A and 1B, the internal cavity 16 of the cartridge 10 can have a diameter 17, and the cartridge can be generally cylindrical. In another aspect, the longitudinal length 13 of the internal cavity 16 of the column 10 can range from about 1cm to about 100 cm. In yet another aspect, the longitudinal length 13 of the internal cavity 16 of the column 10 can range from about 5cm to about 20 cm.

In yet another aspect, the cartridge 10 can include an inlet 18 in fluid communication with the internal cavity 16. In this aspect, the inlet 18 may be configured to receive at least one fluid. In yet another aspect, the cartridge 10 can include an outlet 20 in fluid communication with the internal cavity 16. In an exemplary aspect, and as depicted in fig. 1A, the outlet 20 may be spaced from the inlet 18 along the longitudinal axis 12 of the column 10.

In another aspect, and referring to fig. 2A-5B, the column 10 can include at least one divider 50, the at least one divider 50 positioned within the interior cavity 16. In this aspect, it is contemplated that each divider 50 of the at least one divider may extend along at least a portion of the longitudinal length 13 of the interior cavity 16. In another aspect, the at least one divider 50 may be configured to divide the packing material 40 and direct the flow of fluid through the interior cavity 16 of the column 10. It is contemplated that the at least one divider 50 may be configured to limit the formation of preferred pathways and quiescent zones within the packing material 40 and thereby maintain laminar flow through the interior cavity 16 of the column 10. It is also contemplated that the at least one divider 50 may be enlarged in a corresponding manner with respect to the column 10 to provide similar benefits regardless of the size of the column.

In yet another aspect, at least one divider 50 is selectively spaced from the inlet 18 of the column. In another aspect, at least one divider 50 can be selectively spaced from the column outlet 20. In a still further alternative aspect, the at least one divider 50 can be spaced from both the inlet 18 and the outlet 20 of the column.

Optionally, in one aspect, at least one divider 50 may be secured to the periphery 14 of the column 10. Alternatively, in another aspect, the column 10 may further include an inlet shield plate coupled to the inlet of the column and an outlet shield plate coupled to the outlet of the column, and the at least one divider may be secured to at least one of the inlet shield plate and the outlet shield plate.

In yet another aspect, the at least one divider 50 may comprise a plurality of dividers. In this aspect, it is contemplated that the plurality of dividers 50 can include two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or more dividers. In one aspect, as depicted in fig. 2A-4B, it is contemplated that each divider 50 of the plurality of dividers can extend inwardly from or near the periphery 14 of the column 10 generally orthogonal to the longitudinal axis 12 of the column. In another aspect, at least two dividers 50 of the plurality of dividers can intersect within the interior cavity 16 of the column 10. In this regard, it is contemplated that all of the plurality of dividers 50 can intersect within the interior cavity 16 of the column 10. In an exemplary aspect, as depicted in fig. 4A-4B, the plurality of dividers 50 can extend generally helically along the longitudinal length 13 of the interior cavity 16 of the column 10.

It is contemplated that the at least one divider 50 may comprise a material similar or identical to the material of the column 10. It is also contemplated that the at least one divider 50 may comprise a material similar or identical to the material of the filler material 40. In some aspects, the cartridge 10 and the packing material 40 may comprise different materials. However, it is also contemplated that the cartridge 10 and the packing material 40 may comprise similar or identical materials.

In various aspects, and as depicted in fig. 2C, each divider 50 of the at least one divider may have a longitudinal length 52, a width 54, and a thickness 56. In one exemplary aspect, as shown in fig. 1B, it is contemplated that the periphery 14 of the column 10 can have a thickness 11, and the thickness of the periphery of the column can be approximately equal to the thickness 56 of each divider 50 of the at least one divider. In another exemplary aspect, the ratio of the longitudinal length 52 of each divider 50 to the longitudinal length 13 of the internal cavity 16 of the column 10 can range from about 0.1:1.0 to about 1.0:1.0, including 0.2:1.0, 0.3:1.0, 0.4:1.0, 0.5:1.0, 0.6:1.0, 0.7:1.0, 0.8:1.0, 0.9:1.0, and all ratios therebetween. In further exemplary aspects, the ratio of the width 54 of each divider 50 to the diameter 17 of the internal cavity 16 of the column 10 can range from about 0.1:1.0 to about 1.0:1.0, including 0.2:1.0, 0.3:1.0, 0.4:1.0, 0.5:1.0, 0.6:1.0, 0.7:1.0, 0.8:1.0, 0.9:1.0, and all ratios therebetween.

In one exemplary and non-limiting aspect, the plurality of dividers 50 can include at least one divider that extends along substantially the entire longitudinal length 13 of the interior cavity 16 of the column 10. In this regard, it is contemplated that the plurality of dividers 50 can also include at least one divider that extends along only a portion of the longitudinal length 13 of the interior cavity 16 of the column 10. In another exemplary and non-limiting aspect, the plurality of dividers 50 can be staggered along the longitudinal length 13 of the interior cavity 16 of the column 10.

In another aspect, as shown in fig. 5A-5B, when the column 10 is generally cylindrical, the at least one divider 10 can include at least one cylindrical divider 50, the at least one cylindrical divider 50 having a longitudinal axis and a diameter 58. In this aspect, the diameter 58 of each of the at least one cylindrical divider 50 may be less than the diameter 17 of the interior cavity 16 of the column 10. It is contemplated that each cylindrical divider 50 may be secured within the interior cavity 16 of the column 10 such that the longitudinal axis of the cylindrical divider is generally aligned with the longitudinal axis 12 of the column 10. It is also contemplated that the longitudinal axis of the at least one cylindrical divider 50 may be coincident and collinear with the longitudinal axis 12 of the column 10.

In an exemplary aspect, and referring to fig. 5A and 5B, the at least one cylindrical divider 50 may comprise a plurality of cylindrical dividers having progressively increasing diameters. In this aspect, a plurality of cylindrical dividers 50 can be secured within the interior cavity 16 such that the cylindrical dividers are radially spaced from one another relative to the longitudinal axis 12 of the column.

In another exemplary aspect, it is contemplated that the at least one divider 50 can include at least one cylindrical divider, and at least one divider extending inwardly from the periphery 15 of the column 10, as discussed herein.

In one aspect, the filler material 40 may include at least one of metal, ceramic, plastic, and glass. In another aspect, the filler material 40 may be formed into at least one of conventional balls, beads, pellets, crumbs, fibers, sponges, and pads. In an exemplary aspect, the filler material 40 can be one of glass and a non-reactive metal (e.g., stainless steel). In another exemplary aspect, the filler material 40 may be one of borosilicate glass beads and stainless steel beads. In another aspect, when the filler material 40 comprises beads, the beads may have a diameter ranging from about 20 microns to about 2,000 microns. In yet another aspect, the beads can have a diameter ranging from about 50 microns to about 1,000 microns. In yet another aspect, the beads can have a diameter ranging from about 300 microns to about 800 microns.

In operation, the disclosed cartridge can be used in a method of preparing an emulsion. In one aspect, a method includes positioning a packing material within a column. In another aspect, a method includes introducing a plurality of fluids through an inlet of a cartridge. In this regard, it is contemplated that multiple fluids may be combined within the internal cavity of the cartridge to form an emulsified product. In another aspect, the method includes collecting the emulsified product through an outlet of the cartridge. As used herein, the term "emulsified product" may refer to any emulsion resulting from the mixing of multiple fluids, including emulsions consisting of a continuous phase surrounding a dispersed phase containing an active agent. In one exemplary non-limiting aspect, the emulsified product can include a dissolved active agent in the dispersed phase. In another exemplary non-limiting aspect, the emulsified product can include a suspending active agent in the dispersed phase. In a further exemplary non-limiting aspect, the emulsified product can include a dispersed active in the dispersed phase. In one aspect, it is contemplated that the emulsified product may include a microsuspension that contains an active agent.

In some exemplary aspects, it is contemplated that the plurality of fluids may include a first phase and a second phase. The first and second phases of the plurality of fluids may be any two fluids that are immiscible with each other. In one aspect, it is contemplated that the first phase may serve as the dispersed phase, while the second phase may serve as the continuous phase surrounding the first phase. If a third phase is utilized in the production of the microparticles, the resulting product from the first and second phases is combined with the third phase. In this case, the product from the combination of the first and second phases and the third phase may be any two fluids that are immiscible with each other.

In these aspects, it is contemplated that the first phase can include a solvent and an active agent. The solvent for the first phase may be any organic or aqueous solvent. Examples of solvents include, but are not limited to, water, methylene chloride, chloroform, ethyl acetate, benzyl alcohol, diethyl carbonate, methyl ethyl ketone, and mixtures thereof. In an exemplary aspect, the solvent is ethyl acetate or dichloromethane. In one aspect, the first phase may include a solution of a biodegradable polymer, and a biological or chemical agent as a solution or suspension. Alternatively, it is contemplated that the biological or chemical agent may be dissolved or suspended in the second phase.

It is also contemplated that the second phase may include a solvent. The solvent for the second phase may be any organic or aqueous fluid that is immiscible with the first phase. Examples include, but are not limited to, water, aqueous based solutions, organic solvents, and the like. In an exemplary aspect, the second phase can comprise water, an emulsion stabilizer, and optionally a solvent. In another exemplary aspect, the second phase may comprise water, one or more biological or chemical agents, and optionally a water soluble polymer. In yet another exemplary aspect, the second phase may comprise a second organic solvent, one or more biological or chemical agents, and a polymer.

It is further contemplated that the third phase may include a solvent when used within the scope of the disclosed methods. In one aspect, the solvent of the third phase may be any organic solvent or water.

In one aspect, the solvents of the first and second phases may be selected from the group consisting of: dichloromethane, chloroform, ethyl acetate, benzyl alcohol, diethyl carbonate, methyl ethyl ketone, and water.

The active agent of the present invention may be any biological or chemical agent. Examples of biologically or chemically active agents include, but are not limited to, antibodies, peptides, proteins, enzymes, fusion proteins, porphyrins, nucleic acids, nucleosides, oligonucleotides, RNA, DNA, siRNA, RNAi, aptamers (aptamers), and small molecule drugs. Other bioactive agents include, but are not limited to, stains, lipids, cells, and viruses. The biological agent used in the present invention may be any agent that is capable of having an effect when administered to an animal or human. In one aspect, it includes, but is not limited to, organic molecules, inorganic molecules, anti-infective agents, cytotoxins, anti-hypertensive agents, antifungal agents, anxiolytic agents, anti-inflammatory agents, antineoplastic agents, anti-tubulin agents, neuroleptic agents, antibodies, proteins, peptides, anti-diabetic agents, immunostimulating agents, immunosuppressive agents, antibiotics, antiviral agents, anticonvulsants, antihistamines, cardiovascular agents, anticoagulants, hormones, antimalarials, analgesics, anesthetics, nucleic acids, steroids, aptamers, blood clotting factors, hematogenic factors, cytokines, interleukins, colony stimulating factors, growth factor analogs, fragments thereof, and the like. In another aspect, the biological agent comprises a PEGylated bioactive agent. In yet another aspect, the bioactive molecule is conjugated to a non-toxic, long-chain, hydrophilic, hydrophobic, or amphiphilic polymer. In another aspect, a bioactive agent such as insulin is conjugated to polyethylene glycol.

Exemplary chemical agents can be any synthetic or natural agent, including, for example and without limitation, antioxidants, porosity enhancers, solvents, salts, cosmetics, food additives, textile chemicals, agrochemicals, plasticizers, stabilizers, pigments, opacifiers, adhesives, biocides, fragrances, anti-fouling agents, dyes, oils, inks, catalysts, detergents, curing agents, flavorings, food, fuels, herbicides, metals, paints, photographic agents, biocides, pigments, plasticizers, propellants, solvents, stabilizers, polymer additives, and the like.

Thus, it is contemplated that the active agent of the first phase may be selected from the group consisting of: antioxidants, pore enhancers, solvents, salts, cosmetics, food additives, textile chemicals, agrochemicals, plasticizers, stabilizers, pigments, opacifiers, adhesives, insecticides, fragrances, antifouling agents, dyes, salts, oils, inks, cosmetics, catalysts, detergents, curing agents, flavorings, food, fuels, herbicides, metals, paints, photographic agents, biocides, pigments, plasticizers, propellants, solvents, stabilizers, polymer additives, organic molecules, inorganic molecules, anti-infective agents, cytotoxins, anti-hypertensives, antifungal agents, anxiolytic agents, antibodies, proteins, peptides, anti-diabetic agents, immunostimulants, immunosuppressive agents, antibiotics, antiviral agents, anticonvulsants, antihistamines, cardiovascular agents, anticoagulants, hormones, antimalarials, analgesics, anesthetics, nucleic acids, anti-diabetic agents, anti-inflammatory agents, anti-, Steroids, aptamers, hormones, steroids, blood clotting factors, hematogenic factors, cytokines, interleukins, colony stimulating factors, growth factor analogs, and fragments thereof. In one aspect, it is contemplated that the emulsified product can comprise a microsuspension comprising the microparticles described herein. In this aspect, it is also contemplated that the micro-suspension of the emulsified product may comprise the active agent of the first phase.

In yet another aspect, the second phase may further comprise an emulsion stabilizer. It is optionally contemplated that the first phase may include an emulsion stabilizer. It is contemplated that the emulsion stabilizer may be selected from the group consisting of: poly (vinyl alcohol), polysorbates, proteins, and poly (vinyl pyrrolidone). In one aspect, the concentration of the emulsion stabilizer may range from about 0% to about 20% of either or both of the first and second phases. In another aspect, the concentration of the emulsion stabilizer may range from about 0.5% to about 5% of either or both of the first and second phases.

In another aspect, at least one of the first phase and the second phase may include a polymer, such as, for example and without limitation, a biodegradable polymer. In this regard, it is contemplated that the polymer may be selected from the group consisting of: poly (d, l-lactic acid), poly (glycolic acid), poly (d, l-lactide-co-glycolide) (PLGA), poly (caprolactone), poly (orthoesters), poly (acetals), and poly (hydroxybutyric acid). In some exemplary aspects, when the polymer is PLGA, it is contemplated that the polymer may have a monomer ratio of lactide to glycolide ranging from about 40:60 to about 100: 0. In one aspect, it is contemplated that the polymer may have a monomer ratio of lactide to glycolide ranging from about 45:55 to about 100: 0. In another aspect, the polymer can include a block copolymer of hydrophilic and hydrophobic polymers. In yet another aspect, it is contemplated that the inherent viscosity of the polymer can range from about 0.1 to about 2.0 dL/g. In yet another aspect, it is contemplated that the inherent viscosity of the polymer can range from about 0.1 to about 1.0dL/g, including, for example and without limitation, 0.15dL/g, 0.30dL/g, 0.60dL/g, and 0.90 dL/g. In still further aspects, it is contemplated that the concentration of the polymer in the first and/or second phase can range from about 1% to about 50% w/w. In yet another aspect, it is contemplated that the concentration of polymer in the first and/or second phase can range from about 5% to about 20% w/w.

A more detailed description of an exemplary process for producing an emulsion is set forth below. In one aspect, a method for producing an emulsion for microparticle production includes: (1) forming a first phase, typically comprising an organic solvent, a polymer, and one or more bioactive agents and/or chemicals; (2) forming a second phase typically comprising water as a second solvent, an emulsion stabilizer, and optionally a solvent; and (3) passing the first and second phases through a cartridge to form an "oil-in-water" emulsion.

In another aspect, a method for producing an emulsion comprises: (1) forming a first phase, typically comprising an organic solvent and an emulsion stabilizer; (2) forming a second phase, typically comprising water as a second solvent, one or more bioactive agents and/or chemicals, and a water-soluble polymer; and (3) passing the first and second phases through a cartridge to form a "water-in-oil" emulsion.

In a third aspect, the present invention provides a process for producing an emulsion by: (1) forming a first phase comprising an organic solvent and optionally an emulsion stabilizer; (2) forming a second phase comprising a second organic solvent, one or more bioactive agents and/or chemicals, and a polymer; and (3) passing the first and second phases through a cartridge to form an organic emulsion.

In yet another aspect, the present invention provides a method for producing an emulsion by: (1) forming a first phase, typically comprising water, one or more bioactive agents and/or chemicals, and an emulsion stabilizer; (2) forming a second phase, typically comprising an organic solvent and a polymer; (3) forming a third phase, typically comprising water, and optionally a stabilizer; (4) passing the first and second phases through a first column to form a "water-in-oil" emulsion; and (5) passing the first emulsion and the third phase through a second column to form a "water-in-oil-in-water" emulsion.

It is contemplated that the use of the disclosed cartridge to form an emulsion ensures uniform droplet and particle size distribution, as well as conditions suitable for a variety of chemical or biological agents. In addition, it is contemplated that the apparatus and method of the present invention can readily produce scaled results. It is also expected that a desired batch of microparticles produced on a small scale in a laboratory can be easily reproduced on a larger manufacturing scale simply by using the same packing material in a column having a larger diameter. Thus, it is expected that once the desired microparticles are produced in the laboratory on a small scale, the cartridge allows for inexpensive and efficient scale-up of the production process.

In one exemplary aspect, the method of the present invention provides a continuous process for manufacturing an emulsion for microparticle production at a wide range of flow rates and volumes. In some aspects, the method involves a process of making microparticles having a predetermined size distribution. In an alternative aspect, the method provides a continuous process for producing microparticles at very low flow rates.

The cartridge and the method of producing particles using the cartridge do not rely on turbulent flow. Rather, the method of the present invention for making microparticles operates at laminar flow rates. It is expected that microparticles having a narrow and reproducibly accurate particle size distribution can be produced using the disclosed methods. In addition, it is contemplated that the microparticles can be produced on a small scale and can be easily scaled up to manufacturing size simply by changing the diameter of the column.

Through the use of the disclosed method, an emulsion is made as two fluids, or phases (typically oil and water), are flowing through the gap inside the filler material. As the two phases are flowing through the bed of packing material, they repeatedly cross the path of each other and the continuous phase (usually water) divides the discontinuous phase (usually oil) into droplets, thus forming an emulsion. The discontinuous phase droplet size is repeatedly reduced until the final droplet size is achieved. Once the discrete droplets have reached a certain size, they will not decrease any further even if they continue to flow through the filler material. The disclosed method allows the formation of a precisely sized emulsion under laminar flow conditions.

The very unique dynamic properties of the filler material allow for continuous production of microparticles at very low flow rates. These low flow rates allow consistent production of high quality microparticles in batches as small as 0.1 grams, which maintain a consistent particle size distribution. In addition, these unique flow dynamics also ensure proportionality from laboratory to manufacturing size batches.

The disclosed cartridge and method of using the cartridge provide an emulsion-based process for making microparticles that is insensitive to flow in the laminar flow region. Unlike turbulent mixer-based processes, the process of the present invention is insensitive to variations in flow rate when operated in a laminar flow region. The flow rate used in the present invention may be any laminar flow rate. In an exemplary aspect, the flow rate of fluid through the cartridge can range from about 10 milliliters/minute to about 50 liters/minute. In another exemplary aspect, the flow rate of fluid through the cartridge may range from about 20 milliliters/minute to about 5 liters/minute.

The disclosed cartridge and method of using the cartridge provide an emulsion-based process for making microparticles that is easily scalable from laboratory to manufacturing size batches. A typical batch may show a 10,000-fold proportionality. In a particular batch, the size of the batch may be chosen from one or more of, but is not limited to, the following: 0.1 g, 1 g, 10 g, 50 g, 100 g, 250 g, 0.5 kg, 1 kg, 2 kg, 5 kg, 10 kg, 15 kg, 20 kg, 25 kg, 30 kg, etc. One way to increase the size of a particulate batch is to increase the diameter of the reservoir. Such an increase will act to increase the volume of emulsion passing through the reservoir, thus directly increasing the size of the batch produced.

The disclosed cartridge and method of using the cartridge provide an emulsion-based process for making microparticles that ensures tight control of particle size distribution. The particle size distribution can be manipulated by: changing the size, shape and type of the filling material; rearranging the inlet or outlet housing; a change in a physical property of the first, second or third phase; changing the length or diameter/width of the column; and the like. For example, the final particle size may be determined by the size of the filler material, such as by the diameter of the glass beads. Additionally, it is contemplated that the length of the column may directly affect the particle size distribution.

It is contemplated that the phases may be introduced into the cartridge by any method. In one aspect, the phase is introduced through a tube or pipe and may be pumped, pressed by a gas or another type of pressure source, fed by gravity, or drawn by a vacuum in communication with the inlet of the cartridge. The liquid phase may be transported by tubes comprising stainless steel, glass or plastic compatible with the solvent and temperature used. The fluid phase may be at ambient temperature, or at a temperature required between proper freezing and proper boiling for a particular fluid. It is contemplated that the disclosed cartridge and methods of using the disclosed cartridge may be utilized at any pressure compatible with the equipment utilized. It is also contemplated that the pressure may be adjusted to the pressure necessary to overcome the resistance of the packing material and provide the flow in the laminar flow region of the column.

The microparticles containing the biological or chemical agent are solvent extracted and collected from the emulsified product in a packed bed apparatus. Such techniques are known in the art. The solvent extraction can be performed by, but is not limited to, the following methods: spray drying, extraction into a tank of water or other fluid, freeze drying, evaporation, and the like.

In various aspects, the disclosed cartridge 10 may be used as part of a packed bed apparatus, as schematically depicted in fig. 6. In an exemplary aspect, the packed bed apparatus may include one or more conventional holding tanks or feed reservoirs for holding the first or second phase. The holding tank or feed reservoir may be jacketed or otherwise equipped to provide temperature control of the first or second phase. Tubing may extend from each holding tank or feed reservoir through the pump and later be merged with tubing from other holding tanks or feed reservoirs near the inlet 18 of the cartridge 10. Additionally, it is contemplated that the packed bed apparatus may include a pump or other device that moves the phase into the column 10 and through the column 10. In some aspects, the phases may flow from the holding tank or feed reservoir into the cartridge 10 without a pump, by simple gravity, by pressure, or by vacuum from other ends of the packed bed apparatus, or the like. The tubing may also include the addition of flow meters, feedback control, flow programming controlled by programmed logic, and the like.

It is contemplated that the disclosed methods work at any temperature within the operating range of the equipment, solvent, and active agent. Factors that determine the appropriate temperature for a particular process include the optimum temperatures for the two phases to be transported through the column. If a third phase is utilized, it is contemplated that the temperature of the first spool may be the same or different than the temperature of the second spool. It is also contemplated that the temperature needs to be such that the two phases remain at the desired viscosity. In addition, the solubility of the polymer and the active molecule may require an increase in temperature in order to produce a complete solution. The temperature may additionally be affected by the stability limits of any biological or chemical agent present in the respective phase. In various aspects, typical operating temperatures may range from about 0 to about 50 degrees celsius. In one aspect, typical operating temperatures may range from about 10 to about 40 degrees celsius. In another aspect, typical operating temperatures may range from about 15 to about 30 degrees Celsius. In yet another aspect, typical operating temperatures may range from about 18 to about 25 degrees Celsius.

It is contemplated that the microparticles produced by the disclosed methods can be used for any purpose. In one aspect, they are administered to a subject. In this regard, it is contemplated that they may be administered to a subject in a single or more doses. It is also contemplated that the microparticles may also be administered in a single dose form that acts to further release the biological or chemical agent over an extended period of time, eliminating the need for multiple administrations.

It is also contemplated that the microparticles produced by the disclosed methods can be stored as a dry material. In the example of administration to a subject, the dry microparticles may be suspended in an injection vehicle prior to such use. The microparticles, when suspended, can then be injected into the subject, or otherwise utilized.

As used herein, an injection carrier ("diluent", "injection medium", "injection solution", "pharmaceutical liquid carrier", "suspension medium", "excipient", "vehicle") is an aqueous or anhydrous liquid used to suspend and inject microparticles. The aqueous injection vehicle comprises water, and at least one of a buffer, a salt, a non-ionic tonicity compound, a viscosity enhancer, a stabilizer, an antimicrobial, and a surfactant. In one aspect, the microparticles may be suspended in an injection solution comprising SDS, Tween20, or mannitol. In an exemplary aspect, the injection vehicle can be 0.5% to 2.5% sodium carboxymethyl cellulose in water. In another exemplary aspect, the injection vehicle can be 0-1.5% (w/w) sodium carboxymethyl cellulose, 0-0.5% (w/w) Tween80 or Tween20, 0-330mM NaCl, 0-10mM sodium phosphate in water at pH 5-9. In another aspect, it is contemplated that the microparticles may be suspended in an injection solution comprising 0.5% SDS. In another aspect, it is contemplated that the injection vehicle may include 0.2% Tween20 in water.

It is contemplated that the size of the particles may vary, ranging from submicron to millimeter in diameter. The particle size is determined in part by the size and shape of the individual packing material particles within the column. Large and non-conforming filler materials generally do not pack as tightly together as smaller filler material particles and create larger gaps for fluid to flow through. Thus, it is expected that larger gaps in the filler material produce larger particles, and smaller gaps in the filler material produce smaller particles. It is also contemplated that the flow rate does not affect the size of the particles produced by a particular cartridge. In one aspect, it is contemplated that the diameter of microparticles produced by the disclosed methods can range from about 1 micron to about 200 microns, thereby facilitating administration to a subject through an injection needle. In another aspect, the diameter of the microparticles produced by the disclosed methods can range from about 10 microns to about 100 microns. In yet another aspect, the microparticles may be less than about 90 microns in diameter. In an exemplary aspect, the diameter of the microparticles produced by the disclosed methods can range from about 25 microns to about 125 microns. In another exemplary aspect, the diameter of the microparticles may range from about 25 microns to about 80 microns. In another aspect, the microparticles produced by the disclosed methods can have an average diameter ranging from about 25 microns to about 80 microns. In yet another aspect, the microparticles may have an average diameter ranging from about 10 microns to about 50 microns. In an exemplary aspect, the microparticles produced by the disclosed methods can have a diameter of less than or equal to about 75% of the inner diameter of a needle used to inject the microparticles into a subject. In another aspect, the diameter of the microparticles may be less than or equal to about 50% of the inner diameter of the needle. In yet another aspect, the diameter of the microparticles may be less than or equal to about 35% of the inner diameter of the needle. In yet another aspect, the diameter of the microparticles may be less than or equal to 25% of the inner diameter of the needle. In yet another aspect, the diameter of the microparticles may be less than or equal to 10% of the inner diameter of the needle.

For medical use, it is contemplated that the diameter of microparticles produced by the disclosed methods can range from about 1 micron to about 200 microns. In another aspect, it is contemplated that the diameter of the microparticles may range from about 1 micron to about 100 microns. In yet another aspect, it is contemplated that the diameter of the microparticles may rangeFrom about 10 microns to about 50 microns. Particle size distribution can be measured by several methods including, but not limited to, laser light diffraction, scanning electron microscopy, visible light microscopy, and conventional electrical detection zone methods. The results can be expressed in particular as mean (average or mode) values, standard deviation or half-width, diameter (d) below which 10%, 50% and 90% of the particles are found₁₀、d₅₀、d₉₀) And the fraction of particles in the given range. Further, the data may be expressed by volume-weighted or quantity-weighted statistics. For the present description, laser diffraction measurements were used, using volume weighted statistics, the mean being expressed as the mean, and d₁₀、d₅₀、d₉₀And the like, as well as fractions within a certain range, are used to describe the particle size distribution.

It is contemplated that the use of the disclosed cartridge to form microparticles can provide a narrow size distribution centered at a desired average diameter with the majority of the particles contained in a desired range. During the final step of particulate manufacture, filtration is typically used to exclude particles having a diameter lower or higher than the desired cutoff. With respect to conventional microparticle production involving turbulent mixing, the particle size distribution is broad, and the productivity in a narrow range may be too low to be economical, so that a wide particle size range becomes necessary. By use of the disclosed cartridges, which operate as described, it is expected that a narrow particle size distribution may be obtained and that a high production rate of particles may be produced in order to achieve a final filtration (sieving) of the desired cut-off diameter. It is also expected that the narrow particle size distribution obtained by the use of the disclosed cartridge can result in more efficient injection of microparticles through a very small needle.

In some aspects, the diameter of microparticles produced using the disclosed methods can range from about 1 micron to about 6 microns. In other aspects, the diameter of microparticles produced using the disclosed methods can range from about 10 microns to about 25 microns. In still other aspects, the diameter of microparticles produced using the disclosed methods can range from about 25 microns to about 80 microns. In one exemplary aspect, the microparticles may have an average diameter of less than about 45 microns. In yet another aspect, the microparticles have an average diameter of about 30 microns. In another aspect, the diameter of the microparticles may range from about 10 microns to about 30 microns. In still further aspects, greater than about 80% of the microparticles can have a diameter ranging from about 25 microns to about 63 microns. In yet another aspect, greater than about 90% of the microparticles may have a diameter ranging from about 25 microns to about 63 microns.

In one aspect, it is contemplated that the microparticles may be of an appropriate size and morphology to allow delivery through needles having small inner diameters, such as 25 gauge needles or finer needles. Particles are referred to herein as "injectable" if they can be aspirated and delivered through a needle without significant clumping of particles or clogging of the needle. In an exemplary aspect, the microparticles can be injected through a 25 gauge needle or finer needle. Microparticles are referred to herein as "injectable" if they can be consistently injected through a needle into a desired site in a subject. In an exemplary aspect, the microparticles may be injected through a 25 gauge needle or finer.

In one aspect particularly suited for medical use, microparticles can be injected through such needles: the needle has a gauge of at least 25 and has a nominal inner diameter of 0.0095 inches (241 microns) or less. In another aspect, the microparticles can be injected through a needle that: the needle has a gauge of at least 27 and has a nominal inner diameter of 0.0075 inches (190 microns) or less. In yet another aspect, the microparticles can be injected through a needle that: the needle has a gauge of at least 29 and has a nominal inner diameter of 0.0065 inches (165 microns) or less. In another aspect, the microparticles can be injected through a needle that: the needle has a gauge of at least 30 and has a nominal inner diameter of 0.0055 inch (140 micrometers) or less. In an exemplary aspect, microparticles can be injected through such a needle when suspended in an injection vehicle at a concentration ranging from about 50mg/ml to about 600 mg/ml: the needle has a gauge of 25, 27, 29 or 30. In another exemplary aspect, microparticles can be injected through such a needle when suspended in an injection vehicle at a concentration ranging from about 50mg/ml to about 200 mg/ml: the needle has a gauge of 25, 27, 29 or 30. In a further exemplary aspect, microparticles can be injected through such a needle when suspended in an injection vehicle at a concentration ranging from about 100mg/ml to about 600 mg/ml: the needle has a gauge of 25 or 27.

In one aspect, it is contemplated that the microparticles produced by the disclosed methods can flow freely without the formation of aggregates and can be easily suspended in an injection vehicle for injection. It is contemplated that free-flowing and/or non-agglomerating powders are convenient because they roll with essentially no friction and can be easily placed in a container and/or suspended or included in a solution suitable for injection. The flowability of the microparticles can be measured by any suitable apparatus, such as by Jenike esheartester (Jenike & Johanson, inc., Westford, Mass.), which measures the direct shear strength of powders and other bulk solid materials. Using jenikesharter, the shear cell (base and ring) is filled with material: applying a vertical load to the covering unit using a weight or a weight medium; and the shear cell ring is pushed horizontally across the foundation, measuring and recording the force required. Other devices used to measure flow include powder rheometers (freeman technology, Worcestershire, UK) which measure the force of a twisted blade along a helical path through a powder sample, thereby establishing the required flow rate and flow pattern. The critical orifice and the angle of repose using the breakout process can also be measured.

It is contemplated that microparticles produced using the disclosed methods can have a core loading sufficient to deliver the bioactive agent to maintain a therapeutically effective level of the bioactive agent for a sustained period of time. In some exemplary aspects, the microparticles may have a core loading ranging from about 2.5% to about 90% by weight of the bioactive agent. In one aspect, the microparticles may have a core loading of greater than or equal to about 5% by weight of the bioactive agent. In another aspect, the microparticles may have a core loading of greater than or equal to about 10% by weight of the bioactive agent. In yet another aspect, the microparticles may have a core loading of greater than or equal to about 15% by weight of the bioactive agent. In another aspect, the microparticles may have a core loading of greater than or equal to about 20% by weight of the bioactive agent. In a further aspect, the microparticles can have a core loading of greater than or equal to about 30% by weight of the bioactive agent.

In some exemplary aspects, it is contemplated that microparticles produced using the disclosed methods can be configured to release the bioactive agent over a period of at least about 1 month to about 12 months. In one aspect, the microparticles can be configured to release the bioactive agent over a period of at least about 3 months to about 6 months. In another aspect, the microparticles can be configured to release the bioactive agent over a period of about 1 week to about 3 months.

It is well known in the art that biodegradable polymer compositions can be varied to affect the sustained release time of a given composition. For example, PLGA having a ratio of 45:55 lactide to glycolide and an inherent viscosity of 0.15dL/g may release drug over a period of one to two weeks. The high glycolide content and low molecular weight, reflected by a relatively low intrinsic viscosity value, results in rapid hydrolysis of the polyester chains with respect to the consequent drug release. On the other hand, 85:15 lactide glycolide PLGA-which has an inherent viscosity of 0.91, reflecting a molecular weight of over 100,000daltons, gives a much longer drug release profile, which can last for more than 6 months.

In one aspect, it is contemplated that microparticles produced using the disclosed methods can have high encapsulation efficiency. It is also contemplated that the particles may have an encapsulation efficiency of greater than or equal to about 80%. In another aspect, the particles can have an encapsulation efficiency of greater than or equal to about 90%. In yet another aspect, the particles can have an encapsulation efficiency of greater than or equal to about 95%. In yet another aspect, the particles may have an encapsulation efficiency of about 100%.

In another aspect, it is contemplated that the microparticles produced by the disclosed methods can have any suitable morphology. In one aspect, the particulates may be solid. In yet another aspect, the microparticles may be smooth or crater-free. In another aspect, the microparticles may be homogeneous or monolithic. In a further aspect, it is contemplated that the microparticles may have a morphology that allows for high core loading, high encapsulation efficiency, low burst, sustained release, and injectability.

It is contemplated that microparticles produced using the disclosed methods can be administered to a patient in need of treatment by injection, nasal, pulmonary, oral, vaginal, or other delivery means. In one aspect, the disclosed methods can be used to deliver a bioactive agent to any desired site, including, but not limited to, the patient's intramuscularly, intradermally, subcutaneously, intraorbitally, intraocularly, intravitreally, intraauricularly, intratympanically, intrathecally, intracavitarily, peritumorally, intratumorally, intraspinally, epidurally, intracranially, and intracardially.

It is contemplated that the microparticles produced by the disclosed methods can release the bioactive agent by any suitable means to allow for controlled release of the bioactive agent. It is also contemplated that the microparticles may release the bioactive agent by volumetric erosion, diffusion, or a combination of both. It is further contemplated that the microparticles may be readily suspendable and injectable, while also being configured to provide increased duration, increased stability, reduced burst, and controlled, sustained, or delayed release of the bioactive agent in the body.

Optionally, a surfactant may be used in order to provide the formulation with the required injectability. In an exemplary aspect, a surfactant can be used to provide a stable emulsion during the process of forming microparticles disclosed herein. In another aspect, surfactants may be used to prevent aggregation during drying of the microparticles. In yet another aspect, the surfactant can be used to prevent aggregation within the injection vehicle during the process of delivering the microparticles. It is contemplated that the surfactant may provide batch-to-batch consistency of the microparticles by forming a thin layer of material around the microparticles that helps prevent clumping. It is also contemplated that any suitable surfactant may be used for these purposes. Suitable surfactants include, but are not limited to, cationic, anionic, and nonionic compounds, such as poly (vinyl alcohol), carboxymethyl cellulose (CMC), lecithin, gelatin, poly (vinyl pyrrolidone), polyoxyethylene sorbitan fatty acid esters (Tween 80, Tween60, Tween 20), Sodium Dodecyl Sulfate (SDS), and the like.

In one exemplary aspect, the microparticles may be formed using an emulsion comprising poly (vinyl alcohol). More specifically, the microparticles may be formed using an emulsion comprising 1.0% poly (vinyl alcohol). In various aspects, the concentration of surfactant in the process medium is established in an amount sufficient to stabilize the emulsion.

In another exemplary aspect, the microparticles may be lyophilized in a solution comprising SDS, Tween20, or mannitol. In a particular aspect, the microparticles can be lyophilized in a solution comprising 7.8% SDS.

In another aspect, the disclosed methods can be used to produce microparticles that include PEGylated insulin. It is contemplated that these microparticles may have less than 5% burst release, greater than 12% drug core loading (w/w) and greater than 80% encapsulation efficiency in vivo and in glass tubes. It is also contemplated that the particles may have an average diameter of less than 45 microns, and that greater than 90% (volume weighted) of the particles may have a diameter ranging from about 25 microns to about 63 microns. It is further contemplated that the microparticles of the present invention can be injected into a subject through 25, 27 and 29 gauge finer needles, whereby insulin plasma levels are maintained for about one week to about four weeks.

Claims (15)

1. A method for preparing an emulsion, the method comprising:

positioning a packing material within a column having a longitudinal axis and a periphery defining an interior cavity, the interior cavity having a longitudinal length; the packing material is configured to permit fluid to flow through the column along the longitudinal axis, the column comprising:

an inlet in fluid communication with the internal cavity;

an outlet in fluid communication with the interior cavity; and

at least one divider positioned within the interior cavity, each divider of the at least one divider extending along at least a portion of a longitudinal length of the interior cavity,

wherein the at least one divider is configured to divide the packing material and direct fluid flow through the interior cavity;

introducing a plurality of fluids through an inlet of the cartridge, wherein the plurality of fluids combine within an internal cavity of the cartridge to form an emulsified product; and

the emulsified product is collected through the outlet of the column.

2. The method of claim 1, wherein the filler material comprises at least one of a metal, a ceramic, a plastic, and a glass.

3. The method of claim 2, wherein the filler material is formed as at least one of balls, beads, pellets, crumbs, fibers, sponges, and pads.

4. The method of claim 1, wherein the plurality of fluids comprises:

a first phase comprising a solvent and an active agent; and

a second phase comprising a solvent.

5. The method of claim 4, wherein the solvent of the first and second phases is selected from the group consisting of: dichloromethane, trichloromethane, ethyl acetate, benzyl alcohol, diethyl carbonate, methyl ethyl ketone and water.

6. The method of claim 4, wherein the second phase further comprises an emulsion stabilizer selected from the group consisting of: poly (vinyl alcohol), polysorbates, proteins, and poly (vinyl pyrrolidone).

7. The method of claim 4, wherein the active agent of the first phase is selected from the group consisting of: antioxidants, pore enhancers, solvents, salts, cosmetics, food additives, textile chemicals, agrochemicals, plasticizers, stabilizers, pigments, opacifiers, adhesives, biocides, fragrances, antifoulants, dyes, oils, inks, catalysts, detergents, curing agents, flavoring agents, food products, fuels, herbicides, paints, photographic agents, biocides, propellants, polymer additives, organic molecules, inorganic molecules, anti-infective agents, cytotoxins, anti-hypertensives, antifungal agents, anxiolytic agents, antibodies, peptides, anti-diabetic agents, immunostimulants, immunosuppressive agents, antibiotics, antiviral agents, anticonvulsants, antihistamines, cardiovascular agents, anticoagulants, hormones, antimalarials, analgesics, anesthetics, nucleic acids, steroids, aptamers, blood clotting factors, hematopoietic factors, cytokines, interleukins, skin cells, skin, Colony stimulating factors, growth factors, and fragments thereof.

8. The method of claim 4, wherein at least one of the first phase and the second phase comprises a polymer.

9. The method of claim 8, wherein the polymer is selected from the group consisting of: poly (d, l-lactic acid), poly (glycolic acid), poly (d, l-lactide-co-glycolide) (PLGA), poly (caprolactone), poly (orthoester), poly (acetal), and poly (hydroxybutyrate).

10. The method of claim 4, wherein the emulsified product comprises a micro-suspension comprising the active agent of the first phase.

11. The method of claim 1, wherein the emulsified product comprises a microsuspension comprising an active agent.

12. The method of claim 1, wherein the emulsified product comprises a continuous phase surrounding a dispersed phase comprising an active agent.

13. The method of claim 12, wherein the active agent is dissolved within the dispersed phase.

14. The method of claim 12, wherein the active agent is suspended within the dispersed phase.

15. The method of claim 12, wherein the active agent is dispersed within the dispersed phase.