PROCESS TO PREPARE MICROPARTICLES, AND, WORK HEAD ASSEMBLY FOR A MIXER THROUGH NON-STATIC FLOW

专利摘要:
process for preparing microparticles, and working head assembly for a mixer by non-static flow. The present invention relates to emulsion-based and double-emulsion-based processes for preparing microparticles. the invention also relates to head assemblies for in-line direct flow mixing devices that can be used to mix two or more fluids. head assemblies can be used with processes to prepare microparticles.
公开号:BR112012015200B1
申请号:R112012015200-9
申请日:2010-12-15
公开日:2021-07-20
发明作者:Gary Winchester；Peter Markland
申请人:Evonik Corporation；
IPC主号:

专利说明:

REFERENCE TO RELATED REQUESTS
This order claims the benefit of Order priority.
Provisional US 61/288,973, filed December 22, 2009, the entire contents of which are incorporated herein by reference. FUNDAMENTALS
Microparticles are particles generally less than 210 millimeters in diameter and are typically spherical. Common microparticles generally comprise a matrix-forming material, such as a polymer. A variety of substances can be encapsulated by microparticles. These substances can be released from the microparticle through various controlled release mechanisms, 15 including mechanisms in which the substance passes through the microparticle matrix over time and also including mechanisms of degradation or release by disruption, in which disruptions of the microparticle matrix degrade or erode over time to release the substance.
Several processes exist for preparing microparticles. Emulsion-based processes for making microparticles generally start with the preparation of two distinct phases: a first phase, typically termed a dispersed phase, which generally comprises a dispersion or solution of an agent, which is the substance to be encapsulated in a polymer dispersion or solution in a first solvent, and a second phase, typically termed a continuous phase, which generally comprises a second solvent that is at least partially immiscible with the first solvent of the dispersed phase. After the first and second phases are prepared, they are combined using static or dynamic mixing to form an emulsion, in which microdroplets from the first phase are dispersed into the continuous phase. The microdroplets are then hardened to form microparticles that contain the agent. The hardening step is carried out by removing the first solvent from the microdroplets, generally by any extraction or evaporation process.
The emulsion-forming step is often carried out using a mixing device. In a specific example, with reference to FIG. 1A, a mixing device comprises a rotor/stator head assembly 1100 having an inlet opening of 1101 for the introduction of liquid and solid materials 1104a, which constitute the combined continuous and dispersed phases within the head assembly 1100. Liquid and solid materials 1104a are drawn into the head assembly 1100 by powerful suction created by a rotor element 1106 comprising rotor blades which are rotated by an axis 1102. The rotor blades are positioned substantially perpendicular to a 1107 stator element. Materials exit the head assembly through the 1103 outlet opening.
Referring now to FIG. 1B, as the liquid and solid materials 1104a are drawn into the head assembly 1100, the centrifugal force created by the rotor element 1106 directs the materials relative to the stator element 1107.
Referring now to FIG. 1C, the materials then pass through perforations in stator element 1107 and are led to the periphery of head assembly 1100. Materials are forced through the perforations of stator element 1107 at a rate that subjects the materials to hydraulic shear intense. The material then exits the head assembly at outlet opening 1103. The mixing action of the head assembly causes the dispersed phase in the continuous phase to form an emulsion comprising microdroplets of the dispersed phase in the continuous phases.
A disadvantage of using a head assembly such as the assembly shown in Figs. 1A-C, is that the general microparticle preparation process can be low yielding and can result in wide particle size distributions. Therefore, there is a need for new mixing kits and processes that use mixing kits that overcome the typical disadvantages often encountered with mixing kits used in microparticle production processes. This need and other needs are met by the present invention. SUMMARY
In one aspect, a process for preparing microparticles is disclosed, comprising: (a) providing a process flow comprising (i) a dispersed phase, comprising a first solvent having a polymer and an agent dissolved or dispersed therein , and (ii) a continuous phase, comprising a second solvent that is partially or fully immiscible with the first solvent, (b) passing the process stream through a screen and into a mixing environment; such that during steps (a) or (b), dispersed phase microdroplets form in the continuous phase, and (c) at least substantially, first solvent is removed from the microdroplets to form the microparticles.
In another aspect, a process for preparing microparticles is disclosed, comprising: (a) providing a process flow comprising: a primary emulsion comprising microdroplets of (i) a first dispersed phase, comprising a first solvent having an agent dissolved or dispersed therein, and (ii) a second dispersed phase, which comprises a second solvent that is partially or fully immiscible in the first solvent and having a polymer dissolved or dispersed therein, and a continuous phase comprising a third solvent, which is partially or fully immiscible with the second solvent, (b) passing the process stream through a screen and into a mixing environment; such that during steps (a) or (b), a double emulsion is formed, and (c) at least substantially, the second solvent is removed from the double emulsion to form the microparticles.
In yet another aspect there is disclosed a head assembly for non-static flow through the mixer, comprising: a structure forming a mixing chamber and defining a fluid inlet opening in communication with the mixing chamber and a fluid outlet opening. fluid in communication with the mixing chamber; a screen mesh extending through the inlet opening, and a rotor positioned within the structure between the screen and the fluid outlet opening such that when the rotor is rotated, fluid is directed from the inlet port. , through the mesh of the screen, to the exit opening.
The advantages of the invention will be demonstrated in part in the description which follows, and in part, will be obvious from the description, or may be illustrated by practicing the aspects described below. The advantages described below will be realized and achieved by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the preceding general description and the following detailed description are only exemplary and explanatory and are not restrictive. BRIEF DESCRIPTION OF THE DRAWINGS
Figs. 1A-C are drawings of a mixing process as performed using a conventional mixing head in a rotor/stator mixer.
FIG. 2A is a drawing of an exemplary head assembly in accordance with the present invention.
Fig. 2B is a drawing of a portion of the head, which is connected to an inlet tube.
FIG. 2C is a drawing of an alternative embodiment of a head portion that is connected to an inlet tube configured as a tube-on-tube.
FIG. 3 is a graph of the particle diameter distribution derived from data obtained from a batch of microparticles from Example 2 described below.
FIG. 4 is a graph of the particle diameter distribution derived from data obtained from a batch of microparticles from Example 4 described below.
FIGs. 5-12 are particle diameter distribution graphs derived from data obtained from batches of microparticles from Example 7 described below. DETAILED DESCRIPTION
Before the present compounds, compositions, composites, articles, devices and/or methods are disclosed and described, it is to be understood that the aspects described below are not limited to specific compounds, compositions, composites, articles, devices, methods or use, for as such they can, of course, vary. It is also to be understood that the terminology used here is for the purpose of describing particular aspects only and is not intended to be limiting.
In this descriptive report and in the claims that follow, reference will be made to a number of terms that will be defined to have the following meanings:
Throughout this descriptive report, unless the context requires otherwise, the word "Understand" or variations such as "comprises" or "comprising" will be understood to imply the inclusion of a declared 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 should be noted that, as used in the descriptive report and the accompanying claims, the singular forms “a”, “an” and “o” include plural references, unless the context clearly indicates otherwise. Thus, for example, reference to "an agent" includes mixtures of two or more of these agents, and the like. “Optional” or “optionally” means that the event or circumstance subsequently described may or may not occur, and that the description includes examples where the event or circumstance occurs and examples where it does not.
Ranges can be expressed here from “over” a particular value, and/or “over” another particular value. When such a range is expressed, another aspect includes starting from a particular value and/or to the other particular value. Likewise, when values are expressed as approximations, through the use of the antecedent “about”, it will be understood that the particular value constitutes another aspect. It will further be understood that the ends of each of the lanes are significant both in relation to another endpoint, and independently of another endpoint.
Compounds, compositions and components that can be used to, can be used in conjunction with, can be used in the preparation for, or are products of the disclosed methods and compositions are disclosed. These and other materials are disclosed herein, and it is understood that, when combined, subsets, interactions, groups, etc. These materials are disclosed, which while specific reference to each individual and various collective combinations and permutations of these compounds may not be explicitly disclosed, each is specifically contemplated and described herein. For example, if a number of different polymers and agents are disclosed and discussed, each and every combination and permutation of polymer and agent is specifically contemplated, unless specifically indicated otherwise. Thus, if a class of A, B, and C molecules are disclosed, as well as a class of D, E, and F molecules and an example of a combination molecule, AD is disclosed, then even if each is not individually recited, each is individually and collectively contemplated. Thus, in this example, each of the combinations of A-E, A-F, B-D, B-E, B-F, C-D, C-E, and C-F are specifically contemplated and should be considered disclosed from the description of A, B, and C; D, E, and F; and the A-D combination example. Likewise, any subset or combination thereof is also specifically contemplated and disclosed. Thus, for example, the subgroup of A-E, B-F, and C-E are specifically contemplated and should be considered disclosed from the description of A, B, and C; D, E, and F; and the -10 combination of example A-D. This concept is applicable to all aspects of this disclosure, including, but not limited to, steps in the 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 any specific modality or combination of modalities of the disclosed methods, and that each such combination is specifically contemplated and should be considered disclosed.
As used herein, a "screen" refers to a porous material through which the process flow of the invention can pass. Screen porosity can vary widely depending on the particular process, as will be discussed below.
As used herein, "mixing environment" refers to mixing conditions in which two or more fluids are mixed to mix the fluids in the process stream, for example, to force a dispersed phase into a continuous phase to form an emulsion. .
As used herein, a "non-static flow through the mixer" refers to a mixer having elements that move within a flowing flow of fluids and/or solids.
In one aspect, the process of the invention comprises (a) providing a process flow comprising (i) a dispersed phase comprising a first solvent having a polymer and an agent dissolved or dispersed therein, and (ii) a continuous phase comprising a second solvent that is partially or totally immiscible with the first solvent, (b) passing the process flow through a screen and into a mixing environment, such that microdroplets comprised of the dispersed phase dispersed in the continuous phase are formed either during the step (a) or (b), or both, and (c) removing the first solvent from the microdroplets to form the microparticles.
In another aspect, the process of the invention comprises (a) -10 providing a process flow comprising: a primary emulsion comprising microdroplets of (i) a first dispersed phase comprising a first solvent having a polymer and a dissolved or dispersed agent therein, and (ii) a second dispersed phase which comprises a second solvent which is partially or fully immiscible with the first solvent, and a continuous phase which comprises a third solvent which is partially or fully immiscible with the second solvent, (b) passing the process flow through a screen and into a mixing environment, such that a double emulsion is formed during step (a) or (b) comprising the first and second phases dispersed in the continuous phase, and (c) remove the first solvent from the double emulsion to form the microparticles. Thus, the process of the invention can be used in both emulsion based and double emulsion based microencapsulation methods.
It has surprisingly been found that, passing the process stream through a porous screen and then subjecting the process stream to a mixing environment, and in certain respects, without a subsequent screen or perforated stator in the mixing environment in itself, a number of advantages are realized. In contrast, with a process using a typical in-line mixing device head, such as those shown in Figs. 1A-C, the first process disclosed passes the process flow through a porous screen, which aids in microdroplet formation prior to the mixing step and/or reduces particles to a certain size. In a typical mixing head, a process stream first enters a mixing environment without first having been sieved and is then propelled by the centrifugal force created by a rotor in the mixing device to a stator and then passes through perforations in the stator (typically macroperforations), as discussed above with reference to Figs. 1A-C. This creates a high shear environment and therefore drives a large population of fine particles, which can reduce yield and increase particle size distribution.
Without wanting to be bound by theory, it is believed that the processes of the invention reduce the energetics of the mixing process, producing a small population of very fine particles along with very large particles. Thus, the process is useful for providing an overall particle size distribution of the final, narrower microparticles. The process of the present invention also provides better yields relative to conventional mixing. The mixing environment of the present invention is believed to cause less shear than the typical high shear mixing environment created with mixers such as those depicted in Figs. 1A-C.
According to the disclosed process, a process stream is first provided which comprises either the dispersed phase together with the continuous phase or a primary emulsion together with the continuous phase. The process stream is prepared by combining the dispersed or emulsion phase together with the continuous phase. Once combined, the mixture of dispersed phase or primary emulsion and continuous phase may or may not be mixed. Likewise, upon supplying the process stream, an emulsion may begin to form, prior to mixing.
The process flow is then passed through a screen, which is porous. Depending on the nature of the process, a variety of screens can be used, which will generally have a pore size ranging from 0.1 to 1000 µm or even larger, but preferably between about 1 to 400 µm. For example, in one aspect, the screen may comprise a nominal range of 5 pore sizes, eg a screen with a mesh size 14 (1.4mm) to mesh size 500 (25 microns) to even larger sizes mesh (smaller nominal pore sizes).
The screen can comprise a variety of materials. In one aspect, the screen is a stainless steel mesh cloth or fabric having the desired pore size. To make such a screen, for example, a sieve screen material can be cut from a desired pore size, such as a 75 micron test sieve (200 mesh) which is typically used for sieving particles. such material is a standard FISHERBRAND US stainless steel test sieve A similar stainless steel 15 mesh fabric is commercially available from Small Parts, Inc. (Miami Lakes, FL), which is a stainless steel mesh sieve, ( 120 mesh or 200 mesh) and is of a flat fabric pattern.
Other suitable screen materials include a variety of types of glass, metal, polymers, and inorganic materials such as silica and alumina. Specific examples of such screens include sintered glass screens or sheets, sintered metal screens or porous silica sheets and screens. Fabrics can also be prepared from porous filter membranes, such as those made from hydrophobic or hydrophilic membrane materials, such as those comprising fluoropolymers, polyethylene, polytetrafluoroethylene, PVDF (polyvinylidene fluoride), PCTE, ester. cellulose, mixed cellulose ester, nitrocellulose, nylon, polycarbonate, metals, silver, gold, stainless steel, silica and alumina materials.
In other aspects, the screen comprises a metal material that has a pore size ranging from about 1 to about 500 µm or greater, more preferably, from about 10 to about 200 µm. In specific examples, the screen may have an average pore size of about 50 to about 150 µm, for example 75 or 125 µm. The screen can be selected based on the intended end use of the microparticle. For example, for a microparticle that can be injected into a living subject, smaller particle sizes may be desirable, and thus a smaller screen may be used.
In other aspects, the screen may be prepared from a tortuous matrix, such as a mixed fibrous membrane of cellulose or nylon ester, a non-woven matrix or a sintered metal, or the glass disk, or can be prepared from a notched template having relatively consistent pore diameters, across a membrane surface, such as precision-perforated organic and inorganic membranes, laser-perforated membranes, inorganic pores (e.g. ANOPORE alumina), and the notched band membrane (eg NUCLEPORE membrane).
The process stream enters a mixing environment where the dispersed phase or primary emulsion is mixed with the continuous phase. During the mixing step, the dispersed phase or primary emulsion is brought into the continuous phase to form microdroplets of the dispersed phase or to form a double emulsion. Microdroplet formation is aided by the sieving step, as discussed above. A variety of methods exist to create a blending environment. Appropriate devices that can be used in the mixing step include, but are not limited to, static mixers and dynamic mixers. Mixers of this type include, for example, stirrers, homogenisers, sonication devices and other process equipment known in the state of the art.
In a further aspect, mixing can be accomplished by pumping together the dispersed phase or primary emulsion and the continuous phase through a length of tube or tubing under conditions sufficient to create a suitable mixture, i.e., sufficient turbulence to induce or increase emulsion formation.
Restriction plates (flow constrictors) and filters can also be used to create the necessary mixing environment. Other suitable mixers include non-motorized turbines and flow indicators such as a ball gauge. Another example is a flow through mixer head, such as those in commercially available mixers, for example, a SIL VERSON mixer (SILVERSON Machines Inc., East Longmeadow, Massachusetts, USA), or, more preferably, a head of the invention disclosed, which is described below. The SIL VERSON mixer can be a commercially available standard mixer without a screen and with a stator after the rotor, or one that has been modified by removing the stator and placing a screen through the inlet opening, as will be discussed below. In one aspect, since the first process flow passes through a screen, it does not pass through a subsequent screen after the mixing environment, or in the mixing environment, but after the first sieving step. In additional aspects, the process flow is passed through two or more screens, which can be the same or different, before entering the mixing environment.
In the disclosed double-emulsion process, the primary emulsion can be formed analogously, that is, by mixing a dispersed phase and a continuous phase together. In one aspect, the primary emulsion can first be formed using the described process and then a double emulsion can be formed using the same disclosed process. Alternatively, primary and double-emulsion emulsions can be created using different mixing methods.
In one aspect, the mixing environment does not comprise a subsequent screen or a perforated stator, such as shown in the mixing devices depicted in Figs. 1A-C. Thus, in some respects, the first process stream is sieved, then enters a mixing environment, and is not sieved or passed through a perforated stator in the mixing environment, in contrast to mixing environments created with mixing devices. rotor/stator type mixing, in which a process stream enters the mixing environment without having been sieved and is then propelled through a perforated stator through the centrifugal force created by the rotor.
Once the emulsion or double emulsion is formed, the solvent for the polymer (first solvent, single emulsion and second solvent, double emulsion) is removed to provide the microparticles. Virtually any method known in the art for removing solvent to provide microparticles can be used. Suitable methods include, but are not limited to, spray drying, lyophilization, air drying, vacuum drying, fluid bed drying, milling, coprecipitation, solvent extraction or a combination thereof. In the case of spray drying, freeze drying, air drying, vacuum drying, fluid bed drying and critical fluid extraction. In the case of milling, the components are mixed in dry form and milled by any method known in the state of the art. In the case of coprecipitation, the components are mixed under organic conditions and processed as described below. Components are mixed and dried using precision nozzles to produce extremely uniform droplets in a drying chamber. Suitable spray drying machines 25 include, but are not limited to, Buchi nozzle, NIRO, APV and Lab-plant spray dryers. Generally, the nature of the solvent removal step can vary widely depending on whether or not the process is a batch process, continuous process or a combination batch-continuous process and whether the process involves a single emulsion or a double emulsion. In one aspect, solvent removal is accomplished by extraction, evaporation or a combination of extraction and evaporation protocol, as discussed below.
In one aspect, the solvent can be removed by extraction followed by evaporation. In accordance with this aspect, a portion of the first solvent is removed by extraction, evaporation and then used to remove substantially all of the remaining solvent from the microdroplets or double emulsion to provide the microparticles. Specifically, the process involves adding the emulsion or double emulsion 40 to an extraction phase to concentrate the dispersed phase or phases or to induce film formation at the interface between the dispersed phase and the continuous phase to form microspheres, preferably by injection of the emulsion or double emulsion into an extraction phase current flow. The extraction phase generally comprises a non-solvent for the polymer and a solvent for the continuous phase components; and a limited solvent for the dispersed phase solvent. In one example, the dispersed phase solvent has a solubility of 0.1% to 25%, by weight of the extraction phase. The process then further involves removing the first solvent from the microspheres using an evaporation process, preferably while the microspheres remain in the extraction stage. The formed microspheres can then be collected, washed, dried and packaged using techniques known in the art. The process can also include the use of separation, or sizing, techniques known in the art for classifying microparticles by size.
According to this aspect, performing extraction and evaporation sequentially is twofold. First, the process can control the rate of solvent removal from the dispersed phase droplets such that the surface and internal structure of the resulting microparticles provide the desired release properties. Second, the process can provide the desired properties of microparticles while minimizing the amount of extraction phase needed and therefore the cost of the total process. In both the solvent removal, extraction and evaporation steps, the solvent can be droplet separation from the dispersed or double-emulsion phase into the surrounding medium. The separation rate is proportional to the concentration gradient of the dispersed phase solvent across the interface that exists between the dispersed phase and the solvent extraction phase, and can therefore be controlled by controlling the concentration of the dispersed phase in the extraction solvent throughout the entire process. This can be controlled by adjusting the total volume of the extraction phase, through further addition of the extraction phase.
Control of solvent removal rate can also be achieved by evaporating solvent from the extraction stage at a rate that is combined with the desired rate of solvent removal during the final stage of the encapsulation process. In general, a low solvent removal rate will produce microparticles that have a dense internal structure, while a fast solvent removal rate will produce microparticles that have a porous internal structure. The relationship between the internal structure and the solvent removal rate depends on factors such as the physicochemical properties of the agent, the polymer (composition and molecular weight), the dispersed phase solvent or solvents, and the concentration of the agent and the polymer in the dispersed phase.
The objective of the extraction phase of this aspect is to affect an initial rapid reduction in solvent in the dispersed phase to establish the desired film and internal structure. Once the desired extent and required extraction rate for a particular formulation has been determined, the minimum amount of extraction phase needed to achieve the desired degree of extraction within the desired extraction time frame and under a given set of conditions can be determined empirically or calculated using known mathematical models. The purpose of the evaporation step is to maintain a relatively high driving force for separating the solvent from the dispersed phase, thus minimizing overall process time. The evaporation rate needed to achieve this goal can be determined by empirical methods or through the use of mathematical models. In a preferred aspect, between about 10% and about 90%, and more preferably between about 20% and 70%, of the solvent is removed by extraction.
According to this aspect, the evaporation step can be carried out using techniques known in the state of the art. Evaporation can be carried out under conditions of atmospheric or reduced pressure, and at room temperature or higher temperatures that do not harm the agent. An example of a continuous evaporation process is one in which the process stream exiting the extraction step is passed through a falling film evaporator or clean membrane.
In another aspect, solvent removal can be carried out using a continuous evaporation process. In accordance with this aspect, the solvent is removed using evaporation only in a continuous process following a continuous emulsification process. No extraction is required, and consequently fewer process flows and process equipment are needed than those including extraction.
According to this aspect, dispersed phase or phases and continuous phase are prepared as described above. Following emulsification, the emulsion or double emulsion is transferred directly to an evaporation process. In a preferred aspect, the emulsion flows into a large tank which is kept under vacuum or reduced pressure, removing solvent vapor. The tank can be heated, for example, using an internal steam coil or external jacket, in order to increase the rate of evaporation. The temperature and/or pressure selected depends on the solvent, polymer, and agent selected, as well as the relative amounts of these materials.
In yet another aspect, the solvent removal step can be carried out using an extracting solvent by membrane separation method. In accordance with this aspect, emulsification is followed first by extraction, then by a membrane separation step to remove the remainder of the solvent after the film-forming extraction step. For example, a dispersed phase solvent selective semipermeable membrane, an ultrafiltration membrane with an appropriate molecular weight cut-off, or a microfiltration membrane of suitable pore size can be used in place of a downstream portion of the tube from from the injection point of the extraction phase, ie the extraction latency tube.
In accordance with this aspect, the rate of solvent removal is controlled by the properties of the membrane and the ability of the fluid phase to hold the solvent. This solvent removal process is preferably carried out on a continuous basis. The membrane separation process also provides precise control over the solvent extraction rate, allowing a skilled technician to create a microencapsulation process having a precise extraction profile and which, for example, can be computer controlled and adjusted during continuous operation, for example by adjusting the flow rate of the surrounding extraction fluid.
In yet another aspect, the solvent removal step can be performed using incremental extraction. In accordance with this aspect, the solvent removal process involves introducing the extraction stage into the emulsion or double-emulsion through multiple feed streams rather than a single feed stream. The extraction phase is thus combined with the emulsion at two or more locations along the extraction latency tube, rather than at one location, preferably in a continuous process.
In this regard, each incremental addition of extraction phase may be equal in its ability to keep solvent from the phase dispersed or the increments may differ. In addition, the position along the extraction latency tube where incremental additions are made can be controlled so that the extraction profile can be carefully programmed. With a sufficient number of extraction stage inputs, the effective extraction process becomes a continuous process, in which the extraction rate is determined by the rate of addition of the extraction stage, ie the dilution of the emulsion.
In this aspect, incremental extraction can be used to remove all solvent to be removed from the microparticle, or a partial extraction process can be followed by an evaporation step to remove the solvent remaining after incremental extraction. The desired degree of extraction within the desired extraction time frame for a given set of conditions can be determined empirically or calculated using mathematical models.
In yet another aspect, the solvent removal process can be carried out using a two-step extraction of the solvent. This solvent extraction process uses only two phases, instead of the typical three phases. The same phase is used both to form the emulsion or double emulsion and to extract the solvent. This process requires less process equipment than a continuous three-phase process for microencapsulation. While inherently simpler, the process requires careful control of process variables as it is usually only a narrow operating window, in which the emulsion or double emulsion is sufficiently stable to form spherical droplets in the dispersed phase before extraction precipitates the polymer.
According to this aspect, there are two primary process conditions that can be used in the extraction. The first condition is to operate at solvent saturation levels, producing a solvent evaporation condition rather than solvent extraction. Solvent is removed from a quench tank, possibly using a vacuum aid. The second condition is to operate at saturation levels below the solvent, producing a solvent extraction condition. The process variables for this condition, however, must be carefully adjusted to provide a metastable emulsion or double emulsion in order to form dispersed phase droplets having the desired diameters and surface characteristics.
When the first solvent is removed using extraction, for example using any of the extraction procedures described above, the extraction phase generally comprises a solvent for the continuous phase components, a limited solvent for the dispersed phase solvent, and a non. solvent for the polymer. The first solvent (or the highest proportion first solvent component if a mixture of solvents are used for the first solvent) should generally have a solubility in the extraction stage of about 0.1% and 25% by weight. When water-insoluble polymers are used, the extraction stage is preferably deionized water. The extraction phase can contain buffers to limit the solubility of the agent in the extraction phase.
Any of the common buffers, such as phosphate, acetate, or tris, are suitable for use with the extraction phase as long as they are compatible with the chosen surfactant system. Salts can also be used, such as sodium chloride, potassium chloride, and the like. When making microparticles for pharmaceutical or biomedical applications, the buffer must also be pharmaceutically acceptable. The buffering system must be selected to provide a pH in the extraction phase that provides the minimum solubility of the active agent.
In another aspect, solvent removal can be carried out entirely or partially using a cryogenic extraction step. This is a process in which a cold extraction medium is used to freeze the polymer, the solvent for the polymer, or both into the emulsion or double emulsion. The cryogenic process provides a greater ability to control the mobility of the agent, keeping it in the microparticle based on the proper selection of solvents and temperatures. Lower temperatures can also stabilize the agent, particularly bioactive agents.
The selection of solvent for the dispersed phase, which includes the third solvent in the case of a double emulsion process used in the process generally depends on the polymer and agent chosen, as well as the particular means of solvent removal to be employed. More than one solvent can be used in the dispersed phase, including, for example, the first and third solvent, which can be the same or different. Organic solvents such as acetone, methyl ethyl ketone, ethyl lactate, ethyl acetate, dichloromethane, ethyl acetate/alcohol mixtures are preferred for use with polyesters such as poly(lactide), poly(glycolic acid), poly(lactide-coglycolide), poly(caprolactone) or combinations thereof, and cellulose ethers, cellulose esters, and acrylics. For other polymers, such as polyethylene glycol, poly(vinyl alcohol), and carboxymethylcellulose, water may be preferred as the first solvent.
The dispersed phase polymer can be from a wide variety of different polymers. Polymers can be homopolymers or copolymers, including block or co- or ter-block polymers, random co- or ter-polymers, star polymers or dendrimers. Any polymer of desired molecular weight can be used, depending on the desired properties of the microparticle. If a high strength polymer is desired, then high molecular weight polymers can be used, for example, to satisfy strength requirements. In other aspects, low or medium molecular weight polymers can be used when, for example, time resorption of the polymer, rather than microparticle strength, is desired. Preferably, the polymers used in the process are both biocompatible and biodegradable.
The molecular weight of the polymer can be important for 5 biodegradable microparticles, as the molecular weight influences the rate of polymer degradation. For a diffusion-release mechanism, the polymer must remain intact until all the agent is released from the polymer and then degraded. The agent can also be released from the polymer as the polymer corrodes. By proper selection of polymeric materials, a polymer formulation can be made such that the resulting polymer exhibits both divisional release and degradation release properties. Molecular weights can be measured by methods known in the art, including gel permeation chromatography, viscosity, light scattering, among other 15 methods.
The polymer can be formulated so as to degrade within a desired period of time once present in a particular medium. In some aspects, the time span can be from around less than a day to around 1 month. Longer time intervals can extend to 6-20 months, including, for example, polymers that degrade from about >0 to about 6 months, or from about 1 to about 6 months. In other aspects, the polymer can degrade over longer time intervals, up to 2 years or more, including, for example, from about >0 to about 2 years, or from about 1 month to about 2 years. A sustained release formulation of the microparticle and agent can release the agent through any of these time periods and under a wide variety of release profiles.
The mechanism of release of the desired agent can influence the choice of polymer. A biocompatible polymer, for example, can be selected so as to release or allow release of an agent therefrom at a desired prescribed time after the microparticle has been administered to a subject. For example, the polymer can be selected to release or allow release of the agent before the agent begins to decrease its activity, as the agent begins to decrease in activity, when the agent is partially decreased in activity, for example, by less than 25%, at least 50%, or at least 75% diminished, when the agent is substantially decreased in activity, or when the agent is completely gone or has no more activity. Specific examples of suitable polymers include one or more of a poly(lactide), a poly(glycolic acid), a poly(lactide-coglycolide), a poly(caprolactone), a poly(orthoester), a poly(phosphazene). ), a poly(hydroxybutyrate) or a copolymer containing a Poly(hydroxybutarate), a Poly(lactide-with-caprolactone), a polycarbonate, a polyesteramide, a polyanhydride, a Poly(dioxanone), a Poly(alkylene alkylate), a copolymer of polyethylene glycol and a polyorthoester, a biodegradable polyurethane, a Poly(amino acid), a polyamide, a polyesteramide, a polyetherester, a polyacetal, a polycyanoacrylate, a poly(polyoxyethylene)/poly(oxypropylene) copolymer, polyacetals, polycetals , 20 polyphosphoesters and polyhydroxyvalerates or a copolymer containing a polyhydroxyvalerate, polyalkylene oxalates, polyalkylene succinates, poly(maleic acid), and copolymers, terpolymers, blends, or mixtures thereof.
Lactide-based polymers can comprise any lactide residue, including all racemic and stereospecific forms of lactide, including, but not limited to, L-lactide, D-lactide, and D,L-lactide, or mixtures thereof. Useful polymers comprising lactide include, but are not limited to poly (L-lactide), poly (D-lactide), and poly (DL-lactide) and poly (lactide-co-glycolide), including poly (L-lactide-co). -glycolide), poly(D-lactide-co-glycolic acid), and poly(DL-lactide-co-glycolide), or copolymers, terpolymers, combinations or mixtures thereof.
Lactide/glycolide polymers can be conveniently made by melt polymerization through ring opening of lactide and glycolide monomers. In addition, racemic polymers DL-lactide, L-lactide, D-lactide are commercially available. L-polymers are more crystalline and resorb slower than DL-polymers. In addition to copolymers comprising glycolide and DL-lactide or L-lactide, copolymers of L-lactide and DL-lactide are commercially available. Homopolymers of lactide or glycolide are also commercially available.
In a particular aspect, when the biodegradable polymer is poly(lactide-co-glycolide), or a mixture of poly(lactide) and poly(glycolic acid), the amount of lactide and glycolide in the polymer may vary. In another aspect, the biodegradable polymer contains 0 to 100% moles, 40 to 100% moles, 50 to 100% moles, 60 to 100% moles, 70 to 100% moles, or 80-100 % by moles of lactide and from 0 to 100% by moles, from 0 to 60% by moles, from 10 to 40% by moles, 20 to 40% by moles, or 30 to 40% by moles of glycolide, where the amount of lactide and glycolide is 100% in mol. In another aspect, the biodegradable polymer can be poly(lactide), 95:5 poly(lactide-co-glycolide), 85:15 poly(lactide-co-glycolide), 75:25 poly(lactide-co-glycolide), 65:35 poly(lactide-co-glycolide), or 50:50 poly(lactide-co-glycolide), where the proportions are molar ratios. Likewise, a poly(lactide-co-caprolactone) can be 0:100 mole%, 40 to 100% mole, 50 to 100% mole, 60 to 100% mole, 70 to 100% mole moles, or 80 to 100% moles of lactide and 0 to 100% moles, 0 to 60% moles, 10 to 40% moles, 20 to 40% moles, or 30 to 40% moles of caprolactone.
The processes described herein can be used to form microparticles from a variety of materials and in some aspects biocompatible and biodegradable materials. "Biodegradable" as defined herein means that the polymer will degrade or erode in vivo to form smaller chemical species, where degradation can result, for example, from chemical, enzymatic and physical processes. The term "biocompatible" is used herein to refer to a polymer and any degradation products of the polymer that are non-toxic to a recipient and do not have deleterious effects on the recipient's body. Examples of suitable biocompatible, biodegradable polymers include many of those discussed above, such as polyesters (polyhydroxy acids), such as poly(lactide)s, poly(glycolic acid)s, poly(lactide-coglycolide)s, poly( lactic acid)s, poly(glycolic acid)s, poly(lactide-co-glycolic acid)s, poly(lactide-co-caprolactone)s, poly(lactide-co-glycolide-caprolactone)s, polyanhydrides, polyorthoesters, and polycaprolactone polyetheresters, polyesteramides, polyphosphazines, polycarbonates, polyamides, and copolymers and mixtures thereof.
Biocompatible, non-biodegradable polymers suitable for use in the processes described herein include polyacrylates, ethylene-vinyl acetate copolymers, modified celluloses such as cellulose ethers and cellulose esters, non-degradable polyurethanes, polystyrenes, polyvinyl chloride, polyvinyl fluoride , poly(vinyl alcohol), poly(vinylimidazole), chlorosulfonate polyolefins, polyethylene oxide, and copolymers and mixtures thereof. Specific examples of such polymers are discussed above.
Virtually any agent that can be released from a microparticle can be used with the invention. The agent can be a bioactive agent or a non-bioactive agent. Examples of non-bioactive agents that can be encapsulated by this method include, but are not limited to, adhesives, pesticides, fragrances, antifouling agents, dyes, salts, oils, paints, cosmetics, catalysts, detergents, curing agents, flavors, foods , fuels, herbicides, metals, paints, photographic agents, biocides, pigments, plasticizers, propellants, solvents, stabilizers, polymer additives, and the like.
Likewise, several types of bioactive agents can be used, which are capable of being released from the polymer into a medium, eg a subject. As used herein, a "bioactive agent" refers to an agent that has biological activity. In some aspects, the biological agent can be used to treat, diagnose, cure, mitigate, prevent (i.e., prophylactically), ameliorate, modulate, or have a favorable effect on another form of a disease, disorder, infection or that is present in a -10 subject. A liquid or solid bioactive agent can be used. Bioactive agents can be water-soluble or water-insoluble, depending on the nature of the disclosed process. In some aspects, the bioactive agent is at least very slightly soluble in water, and preferably sparingly soluble in water. Bioactive agents can include salts of the active ingredient. As such, bioactive agents can be acid, base or amphoteric salts. They can be non-ionic molecules, polar molecules or molecular complexes capable of bonding with hydrogen. The bioactive agent can be included in the compositions in the form of, for example, an uncharged molecule, a molecular complex, a salt, an ether, an ester, an amide, drug conjugated polymer, or other form to provide biological efficacy or physiological activity.
Examples of bioactive agents that can be used include, but are not limited to, small molecules, peptides, proteins such as hormones, enzymes, antibodies, antibody fragments, antibody conjugates, nucleic acids such as aptamers, iRNA, siRNA , DNA, RNA, antisense nucleic acid or the like, Antisense nucleic acid analogues or the like, VEGF inhibitors, macrocyclic lactones, dopamine agonists, dopamine antagonists, low molecular weight compounds, high molecular weight compounds or conjugates of bioactive agents . Bioactive agents contemplated for use in the disclosed compositions include anabolic agents, antacids, anti-asthmatic agents, anticholesterolemic and anti-lipid agents, anticoagulants, anti-convulsants, anti-diarrhea, anti-emetics, anti-infectives including anti-bacterial and anti-microbial agents, anti-inflammatory, anti-manic, anti-metabolic agents antineoplastics, antiobesity agents, antipyretic and analgesic agents, antispasmodic agents, antithrombotic agents, antitussive agents, antiuricemic agents, antianginal agents, antihistamines, appetite suppressants, biologicals, brain dilators, coronary dilators, bronchodilators, cytotoxic agents, decongestion agents , diagnostic agents, erythropoiesis agents, expectorants, gastrointestinal sedatives, hyperglycemic agents, hypnotics, hypoglycemic agents, immunomodulating agents, ion exchange resins, laxatives, min supplements eral, mucolytics, neuromuscular drugs, peripheral vasodilators, psychotropics, sedatives, stimulants, thyroid and antithyroid agents, tissue growth agents, uterine relaxants, vitamins or antigenic materials.
Other bioactive agents include androgen inhibitors, polysaccharides, growth factors, hormones, anti-angiogenesis factors, dextromethorphan, dextromethorphan and noscapine hydrobromide, carbetapentane citrate, clofedianol hydrochloride and chlorpheniramine maleate, phenindamine citrate, pyrilamine malexate , phenylephine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, ephedrine, codeine phosphate, codeine morphine sulfate, mineral supplements, cholestriramine, N-acetylprocainamide, acetaminophen, aspirin, ibuprofen, phenyl hydroxide of propaneamine hydrochloride, caffeine, water aluminum, magnesium hydroxide, peptides, polypeptides, proteins, amino acids, hormones, cytokines, interferons and vaccines.
Still other bioactive agents include, but are not limited to, peptide drugs, protein drugs, therapeutic antibodies, desensitizing materials, antigens, anti-infective agents such as antibiotics, antimicrobial agents, antivirals, antibacterials, antiparasitics, antifungal substances and combinations of same, antiallergenics, androgenic steroids, decongestants, hypnotics, anti-inflammatory steroids, anticholinergics, sympathomimetics, sedatives, miotics, psychic energizers, tranquilizers, vaccines, estrogens, progestational agents, humoral agents, prostaglandins, antispasmodics, 10 analgesics histamines, cardioactive agents, anti-inflammatory drugs, antiparkinsonian agents, antihypertensive agents, β-adrenergic agents, nutritional agents, and benzophenanthridine alkaloids. The agent may further be a substance capable of acting as a stimulant, sedative, hypnotic, analgesic, anticonvulsant, and the like.
Still other bioactive agents include, but are not limited to, analgesics such as acetaminophen, acetylsalicylic acid, and the like; anesthetics such as lidocaine, xylocaine, and the like; anorexics such as dexadrine, phendimetrazine tartrate, and the like; anti-arthritis such as methylprednisolone, ibuprofen, and the like; anti-asthmatics such as terbutaline sulfate, theophylline, ephedrine, and the like; antibiotics such as sulfisoxazole, penicillin G, ampicillin, cephalosporins, amikacin, gentamicin, tetracyclines, chloramphenicol, erythromycin, clindamycin, isoniazid, rifampin, and the like; antifungals such as amphotericin B, nystatin, ketoconazole, and the like; antivirals such as amantadine, acyclovir, and the like; anticancer agents such as cyclophosphamide, methotrexate, etretinate, and the like; anticoagulants such as heparin, warfarin, and the like; anticonvulsants such as phenytoin sodium, diazepam, and the like; antidepressants such as isocarboxazid, amoxapine, and the like; antihistamines such as diphenhydramine HCl, chlorpheniramine maleate, and the like; hormones such as insulin, progestins, estrogens, corticosteroids, glucocorticoids, androgens and the like; tranquilizers such as torazine, diazepam, chlorpromazine HCl, reserpine, chlordiazepoxide HCl, and the like; antispasmodics such as belladonna alkaloids, dicyclomine hydrochloride, and the like; vitamins and minerals such as essential amino acids, calcium, iron, potassium, zinc, vitamin B12, and the like; cardiovascular agents, such as prazosin HCl, -10 nitroglycerin, propranolol HCl, hydralazine HCl, pancrelipase, succinic acid dehydrogenase, and the like; peptides and proteins such as LHRH, somatostatin, calcitonin, growth hormone, glucagon-like peptides, growth releasing factor, angiotensin, FSH, EGF, bone morphogenic protein (BMP), erythropoietin (EPO), interferon, 15 interleukin, collagen, fibrinogen, insulin, Factor VIII, Factor IX, Enbrel®, Rituxan®, Herceptin®, alpha-glucosidase, Cerazyme/Ceredose®, vasopressin, ACTH, human serum, albumin, gammaglobulin, structural proteins, protein products from blood, complex proteins, enzymes, antibodies, monoclonal antibodies, and the like; prostaglandins; nucleic acids; 20 carbohydrates, fats; narcotics such as morphine, codeine, and the like, psychotherapeutics, antimalarials, L-dopa, diuretics such as furosemide, spironolactone, and the like; anti-ulcer drugs such as rantidine HCl, cimetidine HCl, and the like.
The bioactive agent may also be an immunomodulator, including, for example, cytokines, interleukins, interferon, colony stimulating factor, tumor necrosis factor, and the like; allergens such as cat dander, birch pollen, mites, grass pollen, and the like; antigens from bacterial organisms such as Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, Streptococcus pyrogenes,
Corynebacterium diphteriae, Listeria monocytogenes, Bacillus anthracis, Clostridium tetani, Clostridium botulinum, Clostridium perfringens. Neisseria meningitidis, Neisseria gonorrhoeae, Streptococcus mutans. Pseudomonas aeruginosa, Salmonella typhi, Haemophilus parainfluenza, Bordetella pertussis, Francisella tularensis, Yersinia pestis, Vibrio cholerae, Legionella pneumophila, Mycobacterium tuberculosis, Mycobacterium leprae, Treponema pallidum, Leptspirosis, Borreferi interrogans, Leptspirosis and similar; such virus antigens as smallpox, influenza A and B, respiratory syncytial, parainfluenza, measles, HIV, SARS, -10 varicella-zoster, herpes simplex 1 and 2, cytomeglavirus, Epstein-Barr virus, the rotavirus, rhinovirus, adenovirus, virus papilloma, polio virus, mumps, rabies, rubella, coxsackievirus, equine encephalitis, Japanese encephalitis, yellow fever, Rift Valley fever, lymphocyte choriomeningitis, hepatitis B, and the like; such antigens from fungi, protozoa, and parasitic organisms, 15 such as Cryptococcuc neoformans, Histoplasma capsulatum, Candida albicans, Candida tropicalis, asteroids Nocardia, Rickettsia ricketsii, Rickettsia typhi, Mycoplasma pneumoniae, Chlamyda psittaci, Chlamyda psittaci, Chlamydia falmobacei histolytica, Toxoplasma gondii, Trichomonas vaginalis, Schistosoma mansoni, and 20 the like. These antigens can be in the form of whole dead organisms, peptides, proteins, glycoproteins, carbohydrates or combinations thereof.
In another specific aspect, the bioactive agent comprises an antibiotic. The antibiotic can be, for example, one or more of amikacin, gentamicin, kanamycin, neomycin, netilmicin, streptomycin, tobramycin, paromomycin, ansamycins, geldanamycin, Herbimycin, carbacefem, cefpodoxime, carbapenems, ertapenem, doripenem, imipenem/cilastatin , cephalosporins (first generation), Cefadroxil, cefazolin, cephalotin or cephalotin, cephalexin, cephalosporins (second generation), cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cephalosporins (third generation), Cefixime, cefrenoxime, cefdinir , ceftazidime, ceftibutene, ceftizoxime, ceftriaxone, cephalosporins (fourth generation), cefepime, cephalosporins (fifth generation), ceftobiprole, glycopeptides, teicoplanin, vancomycin, macrolides, azithromycin, clarithromycin, diritromycin, tebactinthromycin, erythromycin, erythromycin , aztreonam, penicillins, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, Methicillin, nafcillin, oxacillin, penicillin, piperacillin, ticarcillin, polypeptides, bacitracins, colistin, polymyxin B, quinolones, ciprofloxacin, enoxacin, gatifloxacin, trofloxacin, sulfonaxacin, trofloxacin , mafenide, Prontosil (archaic), sulfacetamide, sulfamethizole, sulfanilimide (archaic), Sulfasalazine, Sulfisoxazole, Trimethoprim, trimethoprim-sulfamethoxazole (Co-trimoxazole) (TMP-SMX), tetracyclines, including demeclocycline, tetracycline, minotracycline and others; arsphenamine, chloramphenicol, clindamycin, lincomycin, Ethambutol, Phosphomycin, fusidic acid, Furazolidone, Isoniazid, Linezolid, metronidazole, mupirocin, Nitrofurantoin, Platensimycin, Pyrazinamide, Quinupristin / Dalphopristine/Dalphopristine, Rifazolin, Mupirocin afamelanotide, cilengitide, or a combination of these. In one aspect, the bioactive agent can be a combination of rifampicin (rifampin in the US) and minocycline.
The microparticles prepared by the disclosed process can be used in a variety of applications, such as cosmetics, agriculture, pharmaceuticals, among others. In a specific aspect, microparticles can be used in pharmaceutical compositions. For pharmaceutical compositions, the agent will generally be a bioactive agent, but it need not be. For example, the release agent can be a non-bioactive substance and still be used in a pharmaceutical composition. A variety of pharmaceutical compositions comprising the microparticle can be conveniently prepared in a desired dosage form, including, for example, a unit dosage form or controlled release dosage form and prepared by any of the methods well known in the art. drugstore. In general, pharmaceutical compositions are prepared by uniformly and intimately binding the microparticle in association with a carrier or a finely divided solid carrier, or both, if necessary. In some aspects, the microparticle itself can be the carrier and/or can be combined with other carriers or additives. Other pharmaceutical carriers can also be used. Examples of solid carriers other than the polymer (if solid) include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Examples of liquid vehicles other than polymer (if liquid) are sugar syrup, peanut oil, olive oil and water. Examples of gaseous carriers include carbon dioxide and nitrogen. Other pharmaceutically acceptable carriers or components that can be mixed with the bioactive agent can include, for example, a fatty acid, a sugar or its salt.
The continuous phase comprises at least one solvent that is totally or partially immiscible with the solvent used in the dispersed phase. Generally, the solvent for the continuous aqueous phase is when the dispersed phase is organic, and the continuous phase is non-aqueous when the dispersed phase is aqueous.
Thus, the emulsion can be an oil-in-water emulsion or a water-in-oil emulsion. Likewise, the double emulsion may comprise either a water-in-oil-in-water double emulsion or an oil-in-water-in-oil double emulsion.
The continuous phase may in some aspects be aqueous and may further comprise at least one surfactant or emulsifying agent. Polyvinyl alcohol (PVA) is a preferred surfactant when water is used as the continuous phase solvent. Other emulsifiers or surfactants that can be used include many emulsifiers, for example, soy lecithin egg or bean lecithin, or synthetic lecithins, such as saturated synthetic lecithins, for example, dimyristoyl phosphatidyl choline, dipalmitoyl phosphatidyl choline or distearoyl phosphatidyl choline or unsaturated synthetic lecithins such as dioleyl phosphatidyl choline or dilinoleyl phosphatidyl choline.
Emulsifiers also include surface active agents such as free fatty acids, fatty acid esters with polyoxyalkylene glycol compounds such as polyoxpropylene and polyoxyethylene glycol; ethers of fatty alcohols with polyoxyalkylene glycols; polyoxyalkylated sorbitan fatty acid esters; soaps; glycerol polyalkylene glycerol stearate; polyoxyethylene ricinoleate; homo and copolymers of polyalkylene glycols; soybean oil, castor oil, polyethoxylated and as well as hydrogenated derivatives; ethers and esters of sucrose or other carbohydrates with fatty acids, fatty alcohols, these being optionally polyoxyalkylated; mono-, di-, and triglycerides of saturated or unsaturated fatty acids, glycerides or soybean oil and sucrose. Other emulsifiers include natural and synthetic forms of bile salts or bile acids, both conjugated to amino acids and unconjugated, such as taurodeoxycholate, and cholic acid.
When the continuous phase comprises a surfactant, the surfactant must be present in a sufficient concentration to form a stable emulsion with the dispersed phase using selected mixing means. For example, if the process relies on low intensity emulsification, such as turbulence tube emulsion (described below), then sufficient surfactant must be present to lower the surface tension of the continuous phase. Preferably, the surfactant should make up between about 0.1 and 20% by weight of the continuous phase.
The continuous phase also preferably includes dispersed phase solvent, which reduces or eliminates separation of solvent from the dispersed phase into the continuous phase during emulsification. The amount of solvent added in the dispersed phase to the continuous phase can vary depending on the specific polymer/agent combination used. Generally, the amount of dispersed phase solvent is between about 5% and 100% of the amount needed to saturate the continuous phase, for example, about 7.5%. As discussed above, the continuous phase, like the extraction phase, can optionally further comprise buffers or salts as discussed above. The continuous phase can be further manipulated by an adjustment of the phase pH.
The invention also relates to head assemblies which can be used in non-static flow blends, for example to blend two or more fluid and/or solid streams, and can be used with the process of the invention. With reference to fig. 2A, a preferred head assembly 3000 for a non-static flow mixer comprises a structure 3100 forming a mixing chamber 3150 and defining a fluid inlet opening 3201 in communication with the mixing chamber 3150 and a fluid outlet opening 3150. fluid 3250 in communication with mixing chamber 3150. Head assembly 3100 comprises a screen mesh 3300 extending through inlet opening 3201. As fluid enters fluid inlet opening 3201, it will first pass through the screen 3300, which extends through fluid inlet opening 3201 before entering mixing chamber 3150. In mixing chamber 3150 there is a rotor 3350 positioned within frame 3100 and between screen 3350 and fluid outlet opening 3250, such that when the rotor is rotated 3350, fluid is directed from inlet port 3201, through screen mesh 3300, to outlet opening 3250. As shown in FIG. 2A, and in contrast to the devices shown in Figs. 1 AC, the head does not have a perforated stator or screen positioned in the mixing chamber itself, after the rotor, or a screen positioned between the rotor and the fluid outlet opening.
Mesh screen 3300 can be made of any convenient material, as discussed above, but is preferably a material that will not erode when it encounters the incoming fluid. Thus, a variety of types of materials can be used in the fabric, but will generally be limited by the special mixing process. The printhead screen can comprise any of these materials discussed above in reference to the screening steps of the process. -10 Screen porosity can vary widely depending on the mixing process in which the head assembly is used. For example, when the head assembly is being used to mix the continuous and dispersed phases of the disclosed process, the screen preferably has a porosity of about 0.1 to about 1000 µm, and more preferably of 15 about 10 to about 500 µm. In specific examples where the head assembly is used with the developed process, the screen has a porosity of about 125 µm or about 75 µm.
In operation, referring again to FIG. 2A, as fluid enters fluid inlet opening 3201, and passes through screen 3300 20 extending through inlet opening 3201, it encounters rotor 3350, which will generally have rotor blades. The rotor 3350 functions to create suction through the inlet opening 3201, mixes the fluid, and directs the fluid to the outlet opening 3250. The rotor may comprise a rotating shaft 3351 to rotate the rotor at a desired speed. Such a 3350 rotor can generally operate at a high number of revolutions per minute, depending on the source driving the rotor. For example, when the head assembly is used with the disclosed process, 3350 rotor speeds can generally range from about 10 revolutions per minute (rpm) to about 12,000 RPM, preferably from about 500 RPM to about of 1200 RPM. The 3350 rotor creates what is referred to above as a mixing environment.
Fluid inlet 3201 and outlet 3250 can be connected to a tubing that can contain fluid flowing into and out of the mixing chamber and 3150, which can connect the mixing step to another step of a particular process. . Referring now to FIG. 2B, fluid inlet opening 3201 may be in communication with fluid inlet tube 3200. Fluid inlet tube 3200 may be divided into or comprise one or more other tubes that may contain fluid from another process. For example, with reference to FIG. 2B, in communication with main inlet tube 3200 is a side inlet tube 3202. Depending on the process, the location of the side inlet tube 3202 may be important, as the location of the side inlet tube 3202 affects when and how two or more fluids will be combined with the fluid flowing through the main inlet tube 3200. For example, when the head assembly is being used in a microencapsulation process, such as the disclosed process, the side inlet tube can be positioned at a distance 3353 from about 0 to about 20 centimeters, preferably from about 0 to about 5.5 cm, and more preferably from about 0 to about 0.6 cm, including for example, 0.32 cm and 0.64 cm.
Referring now to FIG. 2C, fluid inlet opening 3201 may be in communication with a fluid inlet tube 3200 and also in communication with an interior inlet tube 3260 through which a fluid such as dispersed phase may be introduced. Inner inlet tube 3260 is positioned within outer fluid inlet tube 3200. Inner tube 3260 may be secured to the outer tube by any suitable means, such as by means of struts that secure the inner tube within the outer tube. . In this mode, the inner inlet tube 3260 can be positioned a distance 3355 away from the screen. This distance may generally range from 0 to 20 cm, preferably from about 0 to about 5.5 cm, and more preferably from about 0 to about 0.6 cm, including for example, 0.32 cm and 0.64 cm. Distance 3355 can be changed by sliding inner tube 3260 closer to or away from the screen. The position of the inner tube, like the position of the side inlet tube generally affects the point at which two fluids, such as a dispersed phase and a continuous phase, are mixed and therefore can be adjusted accordingly.
With reference to the disclosed process and FIGs. 2A-2C, the dispersed phase can flow through the main inlet tube 3200 (or inner tube 3260), while the continuous phase can flow through the side inlet tube 3202. As the continuous phase flows through the inlet tube side 3202 (or inner tube 3260), the dispersed phase (or the primary emulsion) and the continuous phase are combined, though not necessarily mixed. The combined phases are referred to above as the process flow. The process stream then passes to the 3201 inlet port and through the 3300 screen, which can help microdroplet formation in the emulsion. The process flow then meets the 3350 rotor and is mixed into the mixing environment created by the 3350 rotor. The emulsion or double emulsion is then forced through the 3250 fluid outlet opening and continues through the microencapsulation process. . In some aspects, the next step in accordance with the disclosed process will be the extraction or drying step, in which solvent is partially or completely removed from the microdroplets or double emulsion, to thereby provide the microparticles.
The head assembly can be made, according to any desired method. In a preferred aspect, the head assembly is made by modifying a conventional or commercially available head of a flow-through mixing device, such as a Silverson mixer. The modification involves removing the stator from the head (eg, element 1107 in Figs. 1A-C) and installing the screen, through the fluid inlet opening. EXAMPLES
The following examples are developed in order to provide those skilled in the art with a full disclosure and description of how the compounds, compositions, articles, devices and/or methods claimed herein are made and evaluated, and are intended to be merely exemplary of the invention and are not intended to limit the scope of what the inventors regard as their invention. Efforts have been made to ensure -10 accuracy with respect to numbers (eg quantities, temperature, etc.), but some errors and deviations must be taken into account. Unless otherwise noted, parts are parts by weight, temperature is in °C or room temperature, and pressure is at or near atmospheric. Particle size analysis was performed by laser diffraction and reported sizes are based on mean volume statistics. Example 1. Preparation of a Head Assembly
A head assembly for non-static flow through the mixer was prepared by modifying a commercially available Silverson L4R-TA mixer line head (Silverson Machines Inc., East Longmeadow, Massachusetts, USA) in the following manner. The stator was removed from the Silverson L4R-AT in-line mixer head and a screen having a 75µm or 125 µm pore size that was placed in the inlet (inlet) opening on the bottom plate of the mixer head. The stator (eg component 1107 in Fig. 1A) has been removed from the mixer head. An injection tube for the dispersed phase was placed before the mesh. The injection tube was placed before the screen such that the distance between the injection tube and the screen was either between 0 inch and 0.125 inch or about 0.25 inch. These distances were measured from the side of the screen closest to the injection tube to the tip of the injection tube closest to the screen. The tube diameter for the dispersed phase was either 0.125 inch or 0.25 inch. An injection tube for the continuous phase was carried out in-line with the inlet opening of the operating head assembly. Example 2, Placebo of microparticles prepared using a 125 µm screen
Microparticle batches were prepared from a process using the head assemblies with a 125 µm screen as described in Example 1. The average dispersed phase flow rate (SD) was about 25 g/min and the average rate continuous phase (CP) flow rate was about 200g/min, so the total flow rate through the screen (DP 4-PB rate, g/min) was about 225 g/min. Where indicated, the total flow rate (DP + CP rate) was reduced to either 75% of initial (at about 170 g/min) or 50% of initial (at about 112 g/min), maintaining a ratio from CP flow rate to DP flow rate. The average flow rate of the extraction phase was about 1500 g/min. The polymer concentration in the dispersed phase for all batches was 20% in ethyl acetate. The polymer used was poly(D,L-lactide) with an intrinsic viscosity (IV) of about 0.36 dL/g. The continuous phase was in 2% by weight of polyvinyl alcohol in solution saturated with 7.5% of ethyl acetate (PVA). Particle size data shown in Table 1 were obtained from a hardening bath. The microparticles were collected on a 20 μm screen and then lyophilized. Yields are based on initial polymer input and the weight of microparticles collected after sieving through a 20 micron screen and lyophilization. The 125 µm screen was not used. Table 1 shows the results. These microparticles were "placebo" of microparticles and did not contain an agent. The breadth of a particle size distribution was characterized using not only the D50 parameter, for which 50% of the particles are larger than or smaller than the D50 value, but also Di0, which designates the particle size for which 10% of the particles are smaller than Di0. Likewise, D90 designates the particle size for which 90% of the particles are smaller than the D90 value. The amplitude of the particle size distribution can be characterized by the following formula: = width (D90 - DIO)/D5O. The smaller the amplitude value, the narrower the particle size distribution. Table 1
A particle diameter distribution graph derived from data obtained from batch #00210-119-00 is shown in FIG. 3. Example 3. Placebo of microparticles prepared using 75 μm screen
Microparticle batches were prepared from a process using the head assemblies with a 75 µm screen as described in Example 1. The average dispersed phase flow rate (DP) was about 25 g/min. The mean continuous phase flow rate (CP) was about 200g/min, and the mean dispersed phase flow rate (SD) was 25 g/min. Where indicated, the total flow rate (SD + CP ratio) was reduced to 75% either initial (at about 170 g/min) or 50% initial (at about 112 g/min), maintaining a fixed rate from CP flow rate to DP flow rate.
The average flow rate of the extraction phase was about 1500 g/min. The polymer concentration in the dispersed phase for all batches was 20% in ethyl acetate. The polymer used was poly (D,L-lactide) with an intrinsic viscosity (IV) of about 0.36 dL / g. The continuous phase was in 2% by weight polyvinyl alcohol (PVA) solution saturated with 7.5% ethyl acetate. Particle size data shown in Table 2 were obtained from a hardening bath. The microparticles were collected on a 20 µm screen and then lyophilized. Yields are based on initial polymer input and microparticle weight - collected after sieving through a 20 micron screen and freeze-drying. The 125 µm screen was not used. Table 2 shows the results. These microparticles were “placebo” of microparticles and do not contain an active agent. Table 2
Example 4. Placebo comparison of microparticles prepared using rotor/stator head to a screen/rotor head (lot 00277-039)
Microparticle batches were prepared from a process using a standard rotor/stator head assembly commercially available from Silverson L4R-AT in-line mixer as discussed in Example 1 (SELVERSON L4R-TA unmodified). The average dispersed phase flow rate was about 50 g/min, and the average continuous phase flow rate (CP) was about 250 g/min. The average flow rate of the extraction phase was about 1500 g/min. The polymer concentration in the dispersed phase for all batches was 20% in ethyl acetate. The polymer used was poly (D,L-lactide) with an intrinsic viscosity (IV) of about 0.36 dL / g. The continuous phase was a 2% by weight polyvinyl alcohol (PVA) solution saturated with 7.5% ethyl acetate. Particle size data shown in Table 3 were obtained from a hardening bath. The microparticles were collected on a 20 µm screen and then lyophilized. Yields are based on initial polymer input and the weight of microparticles collected after sieving through a 20 micron screen and lyophilization. The 125 µm screen was not used. Table 3 shows the results. These microparticles were “placebo” of microparticles and do not contain an active agent. For comparison, microparticle placebos were made by a method of the present invention using a 125 micron screen and a rotor speed of 500 rpm. The DP flow rate was about 50 g/min, the CP flow rate was about 250 g/min, and the PE flow rate was about 2500 g/min (lot 00277-039- 00). Table 3

A particle diameter distribution graph derived from data obtained from Lot # 00277-090-00 is shown in FIG. 4. Example 5. Goserelin loaded microparticles prepared using a 125 µm screen
Batch of goserelin loaded microparticles were prepared in a process using the head assemblies with a 125 µm screen as described in Example 1. The theoretical goserelin loading was 10% by weight, and the actual goserelin loading was 4 ,two%. The average dispersed phase (SD) flow rate was about 25 g/min. The average continuous phase (CP) flow rate was about 200g/min. The average flow rate of the extraction phase was about 1500 g/min. The polymer concentration in the dispersed phase for all batches was 20% in ethyl acetate. The polymer used was poly (D,L-lactide) with an intrinsic viscosity (IV) of about 0.36 dL / g. The continuous phase was in 2% by weight polyvinyl alcohol (PVA) solution saturated with 7.5% ethyl acetate. Particle size data were taken from a hardening bath. The microparticles were collected on a 20 µm screen and then lyophilized. Yields are based on initial polymer input and the weight of microparticles collected after sieving through a 20 micron screen and lyophilization. The 125 µm screen was not used. Table 4 shows the results. Table 4
Example 6 - Naltrexone loaded microparticles prepared using a 125 µm screen.
Batches of naltrexone loaded microparticles were prepared in a process using the head assemblies with a 125 µm screen as described in Example 1. The theoretical naltrexone loading was 25% by weight, and the actual naltrexone loading was 20 % by weight. The average dispersed phase (SD) flow rate was about 52 g/min.
The average continuous phase flow rate (CP) was about 249 g/min. The average flow rate of the extraction phase was about 2500 g/min. Polymer concentration in the dispersed phase was 20% in ethyl acetate. The polymer used was poly (D,L-lactide) with an intrinsic viscosity (IV) of about 0.36 dL / g. The continuous phase was in 2% by weight polyvinyl alcohol (PVA) solution saturated with 7.5% ethyl acetate. Particle size data were taken from a hardening bath.
The microparticles were collected on a 20 µm screen and then lyophilized. Yields are based on initial polymer input and the weight of microparticles collected after sieving through a 20 micron screen and lyophilization. The 125 µm screen was not used. Table 5 shows the results. Table 5
Example 7. Variable Parameters in the Process Using Head Sets
Certain process parameters were varied in processes using the modified head assemblies described in Example 1. Microparticles were prepared from a 75:25 poly(lactide-co-glycolide) (75% lactide, 25% glycolide) having an intrinsic viscosity of about 0.4 dl/g. (Available from Lakeshore Biomaterials, 756 Tom Martin Unit Birmingham, AL 35211). The dispersed phase comprised 20% by weight of the polymer in ethyl acetate. The continuous phase consisted of 1% by weight of polyvinyl alcohol in a saturated solution of 7.5% ethyl acetate. The batch size was 10 grams. The microparticles were collected on a 20 µm screen and then lyophilized. Yields are based on initial polymer input and the weight of microparticles collected after sieving through a 20 micron screen and lyophilization. The 125 µm screen was not used. In the set of experiments, the continuous phase flow rate, CP/DP ratio, rotor speed, screen pore size, dispersed phase tube diameter, and dispersed phase tube position, relative to the screen, were all varied in different racing process. The process parameters are shown in Table 6 and 8, and the particle properties observed in particles prepared using these process parameters are shown in Tables 7 and 9, respectively. The screen used with the process parameters presented in Table 6 was 125 µl. The screen used with the process parameters shown in Table 8 was 75 µl. For the process parameters shown in Table 8, the position of the dispersed phase tube was placed at a small distance from the screen. Table 6. Process Parameters
Table 7. Results obtained from process using parameters listed in Table 6

Particle size distribution graphs for Lot # 00339-006 and 00339-027 are shown in Figs. 5 and 6, respectively. These batches were prepared with the dispersed phase tube 0.25 cm away from the screen. The particle size distribution graph for Lot # 00339-033 and 00339-143 are shown in Figs. 7 and 8, respectively. These batches were prepared with the dispersed phase tube at approximately the position of the screen, or about 0 cm away from the screen.
The results in Table 7 show that, when using a 125 micron screen, while changing CP flow rate, tube position, tube diameter, rotor speed and CP / DP ratio, a number of particle sizes could be generated. In general, higher flow rate velocities and smaller tube diameters resulted in smaller particle sizes. In 4 of the 8 formulations, particle sizes less than 130 microns were generated with the 125 micron screen. All batches had exceptionally high yields, greater than 80%. Table 8. Process Parameters
Table 9. Results obtained from process using parameters listed in Table 8

The particle size distribution graph for Lot # 00339-107 and 00339-063 are shown in Figs. 9 and 10, respectively.
These batches were prepared with the dispersed phase tube 0.25 cm away from the screen. The particle size distribution graph for the
Lot # 00339-116 and 00339-069 are shown in Figs. 11 and 12, respectively. These batches were prepared with the dispersed phase tube approximately in the screen position or about 0.125 centimeters away from the screen. The results in Table 9 show that higher PB flow ratios and larger DP tube diameter tend to generate larger particle sizes. Changes in rotor speed, CP/DP or CP flow ratio tended to compensate for the influence of the tube diameter. In general, the low flow rate D90/DI0 batches had D90 sizes of about -1070 microns. The influence of the 75 micron screen generates particles smaller than their pore size is shown here. Using the 75 micron screen helped generate desirable particle sizes that could be used in an injectable microparticle product.
As shown in Table 7 and also Table 9, the microparticle product yields were in excess of 75%. In some cases, yields greater than 90% have been obtained, having acceptable particle size. In no case in the collection was a 125 micron sieving step used to remove the larger particles. Particle size analysis showed, in some cases, an absence of 20 particles larger than 125 microns, while an exceptionally high yield was obtained, for example, in Lot # 00339-063.
Various modifications and variations can be made to the compounds, composite materials, kits, articles, devices, compositions and methods described herein. Other aspects of the composites, composite materials, kits, articles, devices, compositions, and methods described herein will be evident from consideration of the specification and practice of the composites, composite materials, kits, articles, devices, compositions, and methods described herein. . It is intended that the descriptive report and the examples be considered as examples.

权利要求:
Claims (24)
[0001]
1. A process for preparing microparticles, characterized in that it comprises: (a) providing a process stream comprising: (i) a dispersed phase comprising a first solvent having a polymer and an agent dissolved or dispersed therein, and ( ii) a continuous phase comprising a second solvent that is partially or totally immiscible with the first solvent; (b) passing the process stream through a filter and into a mixing environment, without a subsequent filter or perforated stator in the mixing environment; such that during step (a) and/or (b) an emulsion is formed which comprises microdroplets from the dispersed phase in the continuous phase; (c) at least removing the first solvent from the microdroplets to form the microparticles; and said process being carried out without a high shear mixture.
[0002]
2. Process according to claim 1, characterized in that the first solvent is an organic solvent.
[0003]
3. Process according to claim 1 or 2, characterized in that the process stream is not subsequently filtered in the mixing environment.
[0004]
4. Process according to any one of claims 1 to 3, characterized in that the second solvent is an aqueous solvent.
[0005]
5. Process according to any one of claims 1 to 4, characterized in that the continuous phase further comprises a surface-active agent.
[0006]
6. Process according to any one of claims 1 to 5, characterized in that the polymer is a biodegradable or biocompatible polymer.
[0007]
7. Process according to any one of claims 1 to 6, characterized in that the polymer comprises poly(lactide), poly(glycolide), poly(caprolactone) or a copolymer or a mixture thereof.
[0008]
8. Process according to any one of claims 1 to 7, characterized in that the agent is a bioactive agent.
[0009]
9. Process according to any one of claims 1 to 8, characterized in that the solvent removal step is performed by lyophilization or cryogenic extraction.
[0010]
10. Process for preparing microparticles, characterized in that it comprises: (a) providing a process stream, comprising: a primary emulsion, comprising microdroplets of (i) a first dispersed phase, comprising a first solvent having an agent dissolved or dispersed therein, and (ii) a second dispersed phase, comprising a second solvent, which is partially or totally immiscible in the first solvent and having a polymer dissolved or dispersed therein; and a continuous phase comprising a third solvent, which is partially or totally immiscible with the second solvent; (b) passing the process stream through a filter and into a mixing environment such that during steps (a) or (b), a double emulsion is formed comprising the first and second phases dispersed in the continuous phase; and (c) at least removing the second solvent from the double emulsion to form the microparticles, and said process being carried out without high shear mixing.
[0011]
11. Process according to claim 10, characterized in that the first solvent is an aqueous solvent.
[0012]
12. Process according to claim 10 or 11, characterized in that the second solvent is an organic solvent.
[0013]
13. Process according to any one of claims 10 to 12, characterized in that the third solvent is an aqueous solvent.
[0014]
14. Process according to any one of claims 10 to 13, characterized in that the continuous phase further comprises a surface-active agent.
[0015]
15. Process according to any one of claims 10 to 14, characterized in that the polymer is a biodegradable polymer.
[0016]
16. Process according to any one of claims 10 to 15, characterized in that the polymer comprises poly(lactide), poly(glycolide), poly(caprolactone) or a copolymer or a mixture thereof.
[0017]
17. Process according to any one of claims 10 to 16, characterized in that the agent is a bioactive agent.
[0018]
18. Working head assembly for a mixer through non-static flow, characterized in that it comprises: a housing forming a mixing chamber and defining a fluid inlet opening in communication with the mixing chamber and an outlet opening of fluid in communication with the mixing chamber; a screen mesh extending through the inlet opening, and a rotor positioned within the housing between the screen mesh and the fluid outlet opening, such that when the rotor is rotated fluid is directed from the inlet opening through from mesh to mesh screen to the output opening.
[0019]
19. Head assembly according to claim 18, characterized in that there is no screen positioned between the rotor and the fluid outlet opening.
[0020]
20. Head assembly according to claim 18 or 19, characterized in that there is no perforated stator positioned between the rotor and the fluid outlet opening.
[0021]
21. Head assembly according to any one of claims 18 to 20, characterized in that the screen mesh has an average pore size diameter of 0.1 to 1000 μm.
[0022]
22. Head assembly according to any one of claims 18 to 21, characterized in that the screen mesh has an average pore size diameter of 1 to 500 μm.
[0023]
23. Head assembly according to any one of claims 18 to 22, characterized in that the screen mesh has an average pore size diameter of 10 to 200 μm.
[0024]
24. Head assembly according to any one of claims 18 to 23, characterized in that the fluid inlet opening is in communication with a fluid inlet tube.

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同族专利:

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公开号 | 公开日

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WO2011087689A2|2011-07-21|

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JP5791629B2|2015-10-07|

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JP5984903B2|2016-09-06|

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EP2516053A2|2012-10-31|

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KR101862416B1|2018-05-29|

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CA2784287C|2017-07-18|

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CN102985175B|2016-03-09|

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CN102985175A|2013-03-20|

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US20110204533A1|2011-08-25|

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JP2013515059A|2013-05-02|

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WO2011087689A3|2011-11-17|

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KR20120115302A|2012-10-17|

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BR112012015200A2|2018-05-22|

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RU2562263C9|2016-04-27|

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RU2562263C2|2015-09-10|

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US9486416B2|2016-11-08|

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BR112012015200A8|2018-06-26|

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JP2015037792A|2015-02-26|

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RU2012130937A|2014-01-27|

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EP2516053A4|2013-08-21|

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CA2784287A1|2011-07-21|

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ES2764971T3|2020-06-05|

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EP2516053B1|2019-11-20|

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法律状态:
2018-07-03| B25D| Requested change of name of applicant approved|Owner name: EVONIK CORPORATION (US) |

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2018-12-04| B06T| Formal requirements before examination [chapter 6.20 patent gazette]|

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2019-01-08| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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2020-06-16| B07D| Technical examination (opinion) related to article 229 of industrial property law [chapter 7.4 patent gazette]|Free format text: DE ACORDO COM O ARTIGO 229-C DA LEI NO 10196/2001, QUE MODIFICOU A LEI NO 9279/96, A CONCESSAO DA PATENTE ESTA CONDICIONADA A ANUENCIA PREVIA DA ANVISA. CONSIDERANDO A APROVACAO DOS TERMOS DO PARECER NO 337/PGF/EA/2010, BEM COMO A PORTARIA INTERMINISTERIAL NO 1065 DE 24/05/2012, ENCAMINHA-SE O PRESENTE PEDIDO PARA AS PROVIDENCIAS CABIVEIS. |

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2021-03-02| B07G| Grant request does not fulfill article 229-c lpi (prior consent of anvisa) [chapter 7.7 patent gazette]|

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2021-04-13| B06A| Patent application procedure suspended [chapter 6.1 patent gazette]|

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2021-06-08| B09A| Decision: intention to grant [chapter 9.1 patent gazette]|

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2021-07-20| B16A| Patent or certificate of addition of invention granted [chapter 16.1 patent gazette]|Free format text: PRAZO DE VALIDADE: 20 (VINTE) ANOS CONTADOS A PARTIR DE 15/12/2010, OBSERVADAS AS CONDICOES LEGAIS. PATENTE CONCEDIDA CONFORME ADI 5.529/DF, QUE DETERMINA A ALTERACAO DO PRAZO DE CONCESSAO. |

优先权:

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申请号 | 申请日 | 专利标题

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US28897309P| true| 2009-12-22|2009-12-22|

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US61/288,973|2009-12-22|

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US61/288973|2009-12-22|

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PCT/US2010/060473|WO2011087689A2|2009-12-22|2010-12-15|Emulsion-based process for preparing microparticles and workhead assembly for use with same|

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