PCT
`WORLD INTELLEcruAL PROPERTY ORGANIZATION
`International Bureau
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (Pen
`(51) International Patent Classification 6 :
`WO 95/13799
`(11) International Publication Number:
`A61K 9/50
`
`Al
`
`(43) International Publication Date:
`
`26 May 1995 (26.05.95)
`
`, ~
`
`(21) International Application Number:
`
`PCTIUS94/13453
`
`(22) International Filing Date:
`
`18 November 1994 (18.11.94)
`
`(81) Designated States: AU, BG, BR, CA, CN, CZ, Fl, HU, JP,
`KR, NO, NZ, PL, European patent (AT, BE, CH, DE, DK,
`ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE).
`
`(30) Priority Data:
`08/154,409
`081298,787
`08/338,805
`
`19 November 1993 (19.11.93)
`US
`us
`31 August 1994 (31.08.94)
`10 November 1994 (10.11.94) us
`
`Published
`With international search report.
`
`INTERNA-
`(71) Applicant: MEDISORB TECHNOLOGIES
`TIONAL L.P. [US/US]; 6954 Cornell Road, Cincinnati,
`OH 45242 (US).
`
`(72) Inventors: RAMSTACK, J., Michael; 326 W. Orchard Avenue,
`Lebanon, OH 45036 (US). HERBERT, Paul, F.; 4 Oak Hill
`Road, Wayland, MA 01778 (US). S1ROBEL, Jan; 7753
`Brookdale Drive, Westchester, OH 45069 (US). ATKINS,
`Thomas, J.; 11708 Vauk Valley Lane, Cincinnati, OH
`45249 (US). HAZRATI, Azar, M.; 2955 Kimberly Drive,
`Maineville, OH 45039 (US).
`
`(74) Agents: CORNWELL, David, K., S. et al.; Sterne, Kessler,
`Goldstein & Fox, Suite 600, 1100 New York Avenue, N.W.,
`Washington, DC 20005-3934 (US).
`
`(54) Title: PREPARATION OF BIODEGRADABLE MICROPARTICLES CONTAINING A BIOLOGICALLY ACTIVE AGENT
`
`HOSE CLAMP
`POLYPROPYLENE Y CONNECTION
`
`HEMOSTATS
`
`/ ' - SIUCON TUBING-3/8" J.D.
`/ ' - S!LCON TUBING-3/18" I.D.
`
`'fO
`
`PUMP
`
`PUMP
`
`(57) Abstract
`
`. A process for preparing biodegradable microparticles comprising a biodegradable polymeric binder and a biologically active agent.
`A first phase, comprising the active agent and the polymer, and a second phase are pumped through a static mixer into a quench liquid
`to form microparticles containing the active agent. Preferably, a blend of at least two substantially non-toxic solvents, free of halogenated
`hydrocarbons, is used to dissolve or disperse the agent and dissolve the polymer.
`
`LUYE1005
`IPR of Patent No. 6,667,061
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`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international
`applications under the PCT.
`
`AT
`AU
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`CI
`CM
`CN
`cs
`cz
`DE
`DK
`ES
`FI
`FR
`GA
`
`Austria
`Australia
`Barbados
`Belgium
`Burkina Paso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`COte d'lvoire
`Cameroon
`China
`Czechoslovakia
`Czech Republic
`Germany
`Denmark
`Spain
`Finland
`France
`Gabon
`
`GB
`GE
`GN
`GR
`HU
`IE
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LI
`LK
`LU
`LV
`MC
`MD
`MG
`ML
`MN
`
`United Kingdom
`Georgia
`Guinea
`Greece
`Hungary
`Ireland
`Italy
`Japan
`Kenya
`Kyrgystan
`Democratic People's Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`
`MR
`MW
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`SI
`SK
`SN
`TD
`TG
`TJ
`TT
`UA
`us
`uz
`VN
`
`Mauritania
`Malawi
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Slovenia
`Slovakia
`Senegal
`Chad
`Togo
`Tajikistan
`Trinidad and Tobago
`Ukraine
`United States of America
`Uzbekistan
`VietNam
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`W095/13799
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`PCTIUS94/13453
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`Preparation of Biodegradable Microparticles
`Containing a Biologically Active Agent
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`Cross-Reference to Related Applications
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`This is a continuation-in-part of co-pending Application Serial No.
`08/154,409, filed November 19, 1993, and co-pending Application Serial No.
`08/298,787, filed August 31, 1994.
`
`Background of the Invention
`
`1.
`
`Field of the Invention
`
`This invention relates to the preparation of microparticles. More
`particularly, the present invention relates to a method of encapsulating active
`agents to fonn controlled-release microparticles through the use of static
`mixers. The present invention also relates to a solvent system useful in a
`method of encapsulating active agents
`to
`fonn controlled-release
`microparticles. By "microparticles" or "microspheres" is meant solid particles
`that contain an active agent dispersed or dissolved within a biodegradable
`polymer that serves as the matrix of the particle.
`
`2.
`
`Description of the Related Art
`
`A variety of methods is known by which compounds can be
`encapsulated in the fonn of microparticles. It is particularly advantageous to
`encapsulate a biologically active or pharmaceutically active agent within a
`biocompatible, biodegradable, wall forming material (e.g., a polymer) to
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`provide sustained or delayed release of drugs or other active agents. In these
`methods, the material to be encapsulated (drugs or other active agents) is
`generally dissolved, dispersed, or emulsified, using stirrers, agitators, or other
`dynamic mixing techniques, in a solvent containing the wall forming material.
`Solvent is then removed from
`the microparticles and thereafter the
`microparticle product is obtained.
`An example of a conventional microencapsulation process is disclosed
`in U.S. Patent No. 3,737,337 wherein a solution of a wall or shell forniing
`polymeric material in a solvent is prepared. The solvent is only partially
`miscible in water. A solid or core material is dissolved or dispersed in the
`polymer-containing solution and, thereafter, the core-material-containing
`solution is dispersed in an aqueous liquid that is immiscible in the organic
`solvent in order to remove solvent from the microparticles. The substances
`to be encapsulated or embedded are dissolved or dispersed in the organic
`solution of the polymer (phase A), using conventional mixers inclu~ing (in the
`preparation of a dispersion) vibrators, and high speed stirrers, etc. The
`dispersion of phase (A), containing the core material in solution or in
`suspension, is carried out in the aqueous phase (B) again using conventional
`mixers, such as high-speed mixers, vibration mixers or even spray nozzles, in
`which case the particle size of the microgranulates will be determined not only.
`by the concentration of phase (A) but also by the particle sizes obtained.
`Another example of a process in which solvent is removed from
`microparticles containing a substance is disclosed in U.S. Patent No.
`3,523,906. In this process, a material to be encapsulated is emulsified in a
`solution of a polymeric material in a solvent that is immiscible in water and
`then the emulsion is emulsified in an aqueous solution containing a hydrophilic
`colloid. Solvent removal from the microparticles is then accomplished by
`evaporation and the product is obtained.
`In still another process, as disclosed in U.S. Patent No. 3,691,090,
`organic solvent is evaporated from a dispersion of microparticles in an
`aqueous medium, preferably under reduced pressure.
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`Similarly, U.S. Patent No. 3,891,570 discloses a method in which
`microparticles are prepared by dissolving or dispersing a core material in a
`solution of a wall material dissolved in a solvent having a dielectric constant
`of 10 or less and poor IJ.?.iscibility with a polyhydric alcohol, then emulsifying
`in fine droplets through dispersion or solution into the polyhydric alcohol and
`finally evaporating the solvent by the application of heat or by subjecting the
`microparticles to reduced pressure~
`Another example of a process in which an active agent may be
`encapsulated is disclosed in U.S. Patent No. 3,960,757. Encapsulated
`medicaments are prepared by dissolving a wall material for capsules in at least
`one organic solvent, poorly miscible with water, that has a boiling point of
`less than 100°C, a vapor pressure higher than that of water, and a dielectric
`·constant of less than about 10; dissolving or dispersing a medicament that is
`insoluble or slightly soluble in water in the resulting solution; dispersing the
`resulting solution or dispersion to the form of fine drops in a liquid vehicle
`comprising an aqueous solution of a hydrophilic colloid or a surface active
`agent, and then removing the organic solvent by evaporation. The size of the
`fine drops is determined according to the stirring speed, the viscosity of the
`organic solvent solution containing the medicament and the wall material, and
`the viscosity and surface tension of the vehicle.
`Tice et al. in U.S. Patent No. 4,389,330 describe the preparation of
`microparticles containing an active agent by using a two-step solvent removal
`process. This two-step solvent removal process is advantageous because it
`results in microparticles having higher active agent loading and a higher
`quality than techniques in which solvent is removed in a single step. In the
`Tice et al. process, the active agent and the polymer are dissolved in a
`solvent. The mixture of ingredients in the solvent is then emulsified in a
`continuous-phase processing medium that is immiscible with the solvent. A
`dispersion of microparticles containing the indicated ingredients is formed in
`the continuous-phase medium by mechanical agitation of the mixed materials.
`From this dispersion, the organic solvent can be partially removed in the first
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`step of the solvent removal process. After the first stage, the dispersed
`microparticles are isolated from the continuous-phase processing medium by
`any convenient means of separation. Following the isolation, the remainder
`of the solvent in the microparticles is removed by extraction. After the
`remainder of the solvent has been removed from the microparticles, they are
`dried by exposure to air or by other conventional drying techniques.
`Tice et al., in U.S. Patent No. 4,530,840, describe the preparation of
`microparticles containing an anti-inflammatory active agent by a method
`comprising: (a) dissolving or dispersing an anti-inflammatory agent in a
`solvent and dissolving a biocompatible and biodegradable wall forming
`material in that solvent; (b) dispersing the solvent containing the anti-
`inflammatory agent and wall forming material
`in a continuous-phase
`processing medium; (c) evaporating a portion of the solvent from the
`dispersion of step (b), thereby forming microparticles containing the anti-
`inflammatory agent in the suspension; and (d) extracting the remainder of the
`solvent from the microparticles.
`WO 90/13361 discloses a method of microencapsulating an agent to
`form a microencapsulated product, having the steps of dispersing an effective
`amount of the agent in a solvent containing a dissolved wall forming material
`to form a dispersion; combining the dispersion with an effective amount of a
`continuous process medium to form an emulsion that contains the process
`medium and microdroplets having the agent, the solvent, and the wall forming
`material; and adding the emulsion rapidly to an effective amount of an
`extraction medium to extract the solvent from the microdroplets to form the
`microencapsulated product.
`lnterna.tlonal Journal of Pharmaceutics
`Bodmeier, R. et al.,
`43:179-186 (1988), disclose the preparation of microparticles containing
`quinidine or quinidine sulfate as the active agent and poly(D,L-lactide) as the
`binder using a variety of solvents including methylene chloride, chloroform,
`and benzene as well as mixtures of methylene chloride and a water miscible
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`liquid, such as acetone,. ethyl acetate, methanol, dimethylsulfoxide,
`chloroform, or benzene to enhance drug content.
`Beck, L. R. et al., Biology of Reproduction 28: 186-195 ( 1983), disclose
`a process for encapsulating norethisterone in a copolymer of D,L-lactide and
`glycolide by dissolving both the copolymer and the norethisterone in a mixture
`of chloroform and acetone that is added to a stirred cold aqueous solution of
`polyvinyl alcohol to form an emulsion and the volatile solvents removed under
`reduced pressure to yield microcapsules.
`Phase separation or non-solvent induced coacervation is a method
`which has also been employed to prepare microparticles comprised of a
`biodegradable polymeric matrix and a biologically active agent. Many of the
`published procedures for microencapsulation with lactide/ glycolide copolymers
`employ solvent evaporation/extraction techniques, but these techniques are
`mostly suitable for water insoluble drugs because water soluble drugs may
`partially partition into the aqueous phase during the preparation p~ocess. The
`phase separation method, utilizes non-solvents for the polymer and in which
`hydrophilic active agents also are not soluble, is an efficient method of
`encapsulation for these active agents.
`In a conventional phase separation method, a known amount of
`polymer, such as poly(lactide-co-glycolide), PLGA, with a monomeric ratio
`of lactide to glycolide ranging from 100:0 to 50:50, is dissolved in an
`appropriate organic solvent. The solid drug, preferably lyophilized and
`micronized, may be dispersed in the polymer solution, where it is insoluble or
`slightly soluble in the organic solvent. Alternatively, the active agent may be
`dissolved in water, or in water which contains some additives, and emulsified
`in the polymer solution, preferably mainly by sonication, forming a water-in-
`oil emulsion. The resultant suspension or emulsion is then added to a reactor
`and addition of a first non-solvent is initiated at a predetermined rate. A
`turbine mixer installed in the reactor is used to provide moderate mixing. At
`the completion of the phase separation process, the·mixture is transferred into
`a quench tank containing a second non-solvent to solidify the semi-solid
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`microspheres. The hardened microspheres are collected by sieving and are
`washed and stored in a vacuum oven for further drying.
`- Very often the solvents used in the known microencapsulation
`processes are halogenated hydrocarbons, particularly chloroform or methylene
`chloride, which act as solvents for both the active agent and the encapsulating
`polymer. The preSence of small, but detectable, halogenated hydrocarbon
`residuals in the final product, however, is undesirable, because of their general
`toxicity and possible carcinogenic activity. Thus, a need exists to revise the
`known. microencapsulation processes using less toxic and acceptable alternative
`solvents.
`With conventional techniques for the microencapsulation of biological
`or pharmaceutical active agents, such as
`those described above,
`the
`microparticles form when the solvent containing an active agent and a polymer
`is emulsified or dispersed in an immiscible solution by stirring, agitating,
`vibrating, or some other dynamic mixing technique, often for a rel_atively long
`period of time. Such dynamic mixing techniques have several drawbacks.
`For example, it is difficult to eontrol the size of the resulting microparticles,
`or the distribution of sizes obtained. As a consequence, use of dynamic
`mixing also presents problems when preparing microparticles containing
`biological or pharmaceutical agents on a production or commercial scale.
`Particularly, production equipment includes a costly emulsion tank, including
`equipment to stir or agitate the fluids. One of the controlling factors for
`overall process time is the time required to form a homogeneous (uniform)
`emulsion. Increased batch sizes in larger tanks require a longer time to form
`the emulsion, resulting in a longer overall production process time. Longer
`exposure times of the active agent to process solvents and to polymer solutions
`can lead to degradation or deactivation of the active agent. Scale-up to a
`production process from a laboratory emulsion process is particularly difficult
`for microencapsulation of biological or pharmaceutical agents since, as the
`batch and tank size are increased, stir speeds and viscosities within the larger
`tank have to be empirically optimized by trial and error at each stage of the
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`scale-up. Likewise, the phase separation technique is not easily converted into
`a process for producing commercial scale quantities of microparticles because
`processing parameters, i.e., rate of non-solvent addition, agitation conditions,
`and the viscosity of both the active agent/polymer solution and the non-solvent
`must be empirically optimized by trial and error at each stage of scale-up.
`Thus, scale-up of conventional microencapsulation techniques is not only time
`consuming, but imprecise.
`Tests were conducted in an attempt to scale-up a laboratory emulsion
`formation process from small stirred glass reactors to production equipment
`for microparticles containing estradiol benzoate. The shear created by the
`mixer blades determined the particle size of the emulsion; the higher the shear,
`the smaller the particles. Due to the low viscosity of the oil (organic) phase
`in the estradiol benzoate process, low shear is required to produce the large
`emulsion particles which were desired.
`In large reactors it is difficult to
`maintain low shear and still provide uniform mixing. The speed ~t which the
`agitator must tum to provide a uniform tank composition produces a small
`particle size with a broad distribution of sizes. Larger mixing blade diameters
`and multiple mixing blades along the shaft helped to provide better mixing at
`low shear but still produced a very broad distribution of sizes. . Particle size
`control became less reliable as batch size was increased.
`Accordingly, one advantage of the method of preparing microparticles
`of the present invention is that accurate and reliable scaling from laboratory
`to commercial batch sizes can be done, while achieving a narrow and well
`defined size distribution of microparticles containing biologically or
`pharmaceutically active agents. This can be achieved for any suitable
`encapsulation technique including, b.ut not limited to, solvent extraction and
`phase separation. A further advantage of the method of the present invention
`is that the same equipment can be used to form microparticles containing
`active agents of a well defined size distribution for varying batch sizes. Yet
`another advantage of the method of the present invention is that high quality
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`microparticles having a high concentration of active agent can be obtained
`using a single step to remove solvent, or through a phase separation technique.
`
`Summary of the Invention
`
`The present invention relates to a method of preparing microparticles.
`More particularly, the present invention relates to a process for
`preparing biodegradable microparticles comprising a biodegradable polymeric
`binder and a biologically active agent. In one aspect of the invention, a first
`phase,. comprising an active agent and a polymer, and a second phase are
`pumped through a static mixer into a quench liquid to form microparticles
`containing the active agent.
`In a further aspect of the invention, the first
`phase and the second phase are substantially immiscible. In another aspect of
`the invention, the second phase is free from solvents for the polymer and
`active agent, and may be comprised of an aqueous solution of a~ emulsifier.
`The process of the present invention whereby microparticles are prepared
`using static mixers can be used with any conventional encapsulation technique
`including, but not limited to, solvent extraction and phas~. separation.
`In further aspects of the invention, the first phase is prepared by
`dissolving the active agent in a solution containing the polymer, by preparing
`a dispersion comprising the active agent, and by preparing an emulsion
`comprising the active agent.
`In yet further aspects of the invention, the method is used to prepare
`microparticles containing the following active agents: risperidone; trenbolone
`acetate; norethindrone; testosterone; estrodiol benzoate; human serum albumin;
`pig albumin; and recombinant bovine interferon-alpha.
`In a preferred embodiment of the invention, a blend of at least two
`substantially non-toxic solvents, free of halogenated hydrocarbons, is used to
`dissolve both the agent and the polymer. The solvent blend containing the
`dissolved agent and polymer is dispersed in an aqueous solution to form
`droplets. The resulting emulsion is then added to an aqueous extraction
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`medium preferably containing at least one of the solvents of the blend,
`whereby the rate of extraction of each solvent is controlled, whereupon the
`-biodegradable microparticles containing the biologically active agent are
`formed. The process has the advantages that less extraction medium is
`required because the solubility of one solvent in water is substantially
`independent of the other and solvent selection is increased, especially with
`solvents that are particularly difficult to extract.
`In a preferred embodiment, the present invention relates to a solvent
`system· useful in a method of preparing a pharmaceutical composition in
`microparticle form designed for the controlled release of an effective amount
`of a drug over an extended period of time. This composition comprises at
`least one pharmaceutical agent and at least one biocompatible, biodegradable
`encapsulating polymer.
`·More particularly, in yet a further aspect of the invention, the present
`invention relates to a method for preparing microparticles comprjsing:
`A.
`preparing a first phase comprising a biodegradable polymeric
`encapsulating binder and an active agent dissolved or dispersed
`in a blend of at least two mutually miscible organic solvents
`free from halogenated hydrocarbons and having limited water
`solubility,
`preparing a second phase comprising an aqueous solution of
`(1)
`a hydrophilic colloid or
`(2)
`a surfactant,
`combining said first phase and said second phase under the
`influence of mixing means to form an emulsion in which said
`first phase is discontinuous and said second phase continuous,
`and
`isolating said discontinuous first phase in the form of
`microparticles.
`Limited water solubility means having a solubility in water in the range
`of from about 0.1 to about 25 wt. % at 20°C.
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`D.
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`In a preferred embodiment, the present invention relates to a method
`for preparing microparticles comprising preparing a first "oil" phase
`containing from about 5 weight percent to about 50 weight percent solids of
`which from about 5 to about 95 weight percent is a solution of biodegradable
`polymeric encapsulating binder and incorporating from about 5 to about 95
`weight percent, as based on polymeric binder, of an active agent in a solvent
`blend, the blend comprising first and second mutually miscible solvents, free
`from halogenated hydrocarbons, each having a solubility in water of from
`about 0.1 to about 25 weight percent at 20°C, forming an emulsion containing
`from 1: 1 to 1: 10 of the first phase in an emulsion process medium to form
`microdroplets of the first phase composition in a continuous aqueous second
`phase processing medium, adding the combined first and second phases to an
`·aqueous extraction quench liquid at a level of from about 0.1 to about 20 liters
`of aqueous quench liquid per gram of polymer and active agent, said quench
`liquid containing the solvent of the blend having the greater wat~r solubility
`at a level of from about 20% to about 70% of the saturation level of that
`solvent in the quench liquid at the temperature being used, and recovering
`microparticles from the quench liquid.
`In another aspect, the invention is directed to a method of preparing
`microparticles comprising the steps of: preparing a first phase, said first phase
`comprising a biologically active agent, a biodegradable polymer, and a blend
`of at least two mutually miscible solvents for the agent and the polymer free
`from halogenated hydrocarbons; preparing a second phase, wherein said first
`phase is substantially immiscible in said second phase; flowing said first phase
`through a static mixer at a first flow rate; flowing said second phase through
`· said static mixer at a second flow rate so that said first phase and said second
`phase flow simultaneously through said static mixer thereby forming
`microparticles containing said active agent; and isolating said microparticles.
`In another aspect, the invention is directed to a method of preparing
`microparticles comprising the steps of: preparing a first phase, said first phase
`comprising a biologically active agent, a biodegradable polymer, and a blend
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`of at least two mutually miscible solvents for the agent and the polymer free
`from halogenated hydrocarbons; preparing a second phase, wherein said first
`phase and said second phase are substantially immiscible; preparing a quench
`liquid; pumping said first phase and said second phase through a static mixer
`into said quench liquid. thereby forming microparticles containing said active
`agent.
`
`In further aspects of the invention, the first phase is prepared by
`(1) dissolving the biologically active agent in a solution of the polymer
`dissolved in at least two mutually miscible solvents free from halogenated
`hydrocarbons, or (2) by preparing a dispersion comprising the active agent in
`said solvents, or (3) by preparing an emulsion comprising the active agent in
`said solvents.
`
`Brief Description of the Drawings
`
`Figure 1 illustrates flow through a static mixer;
`Figure 2 shows a static mixer which may be used in the process of the
`present invention;
`Figure 3 shows a laboratory set-up for carrying out a preferred process
`for preparing the microparticles of the present invention;
`·Figure 4 depicts a graph of time release animal test data for two
`formulations of norethindrone loaded microparticles;
`Figure 5 depicts a graph of in vitro dissolution data for risperidone
`microparticles of batch Prodex 3, both as produced and lyophilized;
`Figure 6 depicts a· graph of in vitro dissolution data for risperidone
`microparticles of batch Prodex 2, both as produced and lyophilized;
`Figure 7 depicts a graph of accelerated in vitro dissolution data for
`risperidone microparticles of batches Prodex 3 and Prodex 2;
`Figure 8 depicts a graph of mean (n = 2) plasma concentration-time
`curves for an active moiety (sum of risperidone and 9-hydroxy risperidone)
`after single intramuscular administration to beagle dogs of risperidone depot
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`formulations at an approximate dose of 2.5 mglkg. The period of anti-emetic
`activity (in at least 2 out of 3 dogs) in the apomorphine vomiting test is given
`in the legend for each of the formulations. An asterisk(*) indicates that the
`anti-emetic activity is interrupted in at least 2 out of 3 dogs at the beginning
`of the study. The broken line indicates an approximate lowest minimum
`plasma concentration necessary for anti-emetic activity. The I I sign indicates
`that for formulation Prodex 2 no blood was sampled on days 14, 18, and 21;
`Figure 9 depicts a graph of cumulative percent by microparticle size
`of estradiol benzoate loaded microparticles;
`Figure 10 depicts a graph of percent differential by microparticle size
`of estradiol benzoate loaded microparticles;
`Figure 11 depicts a graph of time release animal test data for estradiol
`benzoate loaded microparticles;
`Figure 12 depicts a graph of cumulative percent by microparticle size
`of trenbolone acetate loaded microparticles;
`Figure 13 depicts a graph of time release animal test data for
`testosterone loaded microparticles;
`Figures 14A-C depict three graphs showing the effect of spiking the
`quench liquid with ethyl acetate on norethindrone (NET) microparticle
`characteristics; and
`Figures 15A-C depict three graphs showing the effect of quench
`volume on NET microparticle characteristics.
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`Description of the Preferred Embodiments
`
`The present invention involves the use of a solvent blend, free from
`halogenated hydrocarbons, comprising at least two solvents to produce
`biodegradable microparticles comprising at least one biologically active agent.
`A first solvent component of the solvent blend is a poor solvent for the active
`agent, but is a good solvent for the biodegradable polymer used herein. A
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`SUBSTITUTE SHEET (RULE 26)
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`LUYE1005
`IPR of Patent No. 6,667,061
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`W095/13799
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`PCTIUS94/13453
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`second solvent component of the solvent blend is a good solvent for both the
`active agent and the polymer.
`The method-of the present invention provides advantages over methods
`known in the art. The present method provides, inter alia, a biodegradable
`system, an injectable system that prevents the loss of dose during treatment,
`the ability to mix microparticles containing different drugs, microparticles free
`from halogenated hydrocarbon residues, and the ability to program release
`(multiphasic release patterns) to give faster or slower rates of drug release as
`needed.
`The products prepared by the method of the present invention offer the
`advantage of durations of action ranging from 30 to more than 200 days,
`In a preferred
`depending upon the type of microparticle selected.
`embodiment, the. microparticles are designed to afford treatment to patients
`over a period of 30 to 60 days. The duration of action can be easily
`controlled by manipulation of the polymer composition, polymer.: drug ratio,
`and microparticle size.
`Another important advantage of the microparticles prepared by the
`process of the present invention is that practically all of the active agent is
`delivered to the patient because the polymer used in the method of the
`invention is biodegradable, thereby permitting all of the entrapped agent to be
`released into the patient.
`In the process of the present invention, an active agent is dissolved or
`dispersed in a solvent blend free from halogenated hydrocarbons and to the
`agent-containing medium is added the polymeric matrix material in an amount
`relative to the active agent that provides a product having the desired loading
`of active agent. Optionally, all of the ingredients of the microparticle product
`can be blended in the solvent blend medium together.
`The solvent system used herein is a blend of at least two solvents.
`These solvents must be:
`mutually miscible with one another,
`(1)
`capable, when blended, of dissolving or dispersing the active agent,
`(2)
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`IPR of Patent No. 6,667,061
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`PCTIUS94/13453
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`capable, when blended, of dissolving polymeric matrix material,
`chemically inert to the active agent,
`biocompatible,
`substantially immiscible with the quench liquid, e.g., having a
`solubility of no more than about 0.1 to 25%, and
`solvents other than halogenated hydrocarbons.
`By "halogenated hydrocarbons" is meant halogenated organic solvents,
`i.e.' cl - c4 halogenated alkanes, e.g.' methylene chloride, chloroform,
`methyl chloride, carbon tetrachloride, ethylene dichloride, ethylene chloride,
`2,2,2-trichloroethane, and the like.
`An ideal solvent blend for encapsulation of an active agent should have
`a high solubility for the polymeric encapsulating agent of generally at least
`about 5 weight percent and, preferably, at least about 20 weight percent at
`20°C. The upper limit of solubility is not critical, but if over about 50 weight
`percent of the solution is encapsulating polymer, the solution may _become too
`viscous to handle effectively and conveniently. This is, of course, dependent
`on the nature