(12) United States Patent
`Wright et al.
`
`I 1111111111111111 11111 lllll lllll lllll lllll 111111111111111 1111111111 11111111
`US006264987Bl
`US 6,264,987 Bl
`Jul. 24, 2001
`
`(10) Patent No.:
`(45) Date of Patent:
`
`(54) METHOD FOR PREPARING
`MICROPARTICLES HAVING A SELECTED
`POLYMER MOLECULAR WEIGHT
`
`(75)
`
`Inventors: Steven G. Wright, Madeira; Michael
`E. Rickey, Loveland; J. Michael
`Ramstack, Lebanon; Shawn L. Lyons;
`Joyce M. Hotz, both of Cincinnati, all
`of OH (US)
`
`(73) Assignee: Alkermes Controlled Therapeutics
`Inc. II, Cambridge, MA (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 09/575,075
`
`(22) Filed:
`
`May 19, 2000
`
`(51)
`
`Int. Cl.7 ............................... A61K 9/14; A61K 9/50;
`B0lJ 13/02
`(52) U.S. Cl. .......................... 424/489; 424/497; 424/484;
`264/41; 264/46; 427 /213.3; 427 /213.36
`(58) Field of Search ..................................... 424/489, 497;
`264/41, 46; 427 /213.3, 213.36
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`5,654,008 * 8/1997 Herbert et al. ....................... 424/489
`
`* cited by examiner
`
`Primary Examiner-Thurman K. Page
`Assistant Examiner-Blessing Fubara
`(74) Attorney, Agent, or Firm-Andrea G. Reister;
`Covington & Burling
`
`(57)
`
`ABSTRACT
`
`A method for preparing microparticles having a selected
`polymer molecular weight. The hold time and temperature
`of a solution containing a nucleophilic compound and a
`polymer having a starting molecular weight are controlled in
`order to control the molecular weight of the polymer in the
`finished microparticle product. In this manner, a selected
`polymer molecular weight in the finished microparticle
`product can be achieved from a variety of starting material
`molecular weights.
`
`50 Claims, 4 Drawing Sheets
`
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`
`APOTEX EXHIBIT 1007
`Apotex v. Alkermes
`IPR2025-00514
`
`

`

`U.S. Patent
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`Jul. 24, 2001
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`Jul. 24, 2001
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`

`US 6,264,987 Bl
`
`2
`of the polymer or polymeric matrix material in the finished
`microparticle product. There is a particular need in the art for
`an improved process that provides a method for preparing
`microparticles that have a selected polymer molecular
`5 weight. The present invention, the description of which is
`fully set forth below, solves the need in the art for such an
`improved method.
`
`1
`METHOD FOR PREPARING
`MICROPARTICLES HAVING A SELECTED
`POLYMER MOLECULAR WEIGHT
`BACKGROUND OF THE INVENTION
`1. Field of the Invention
`The present invention relates to preparation of micropar(cid:173)
`ticles. More particularly, the present invention relates to a
`method and an apparatus for preparing microparticles hav(cid:173)
`ing a selected polymer molecular weight.
`2. Related Art
`A variety of methods is known by which compounds can
`be encapsulated in the form of microparticles. It is particu(cid:173)
`larly advantageous to encapsulate a biologically active or
`pharmaceutically active agent within a biocompatible, bio(cid:173)
`degradable wall forming material (e.g., a polymer) to pro(cid:173)
`vide 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 20
`dynamic mixing techniques, in one or more solvents con(cid:173)
`taining the wall forming material. Solvent is then removed
`from the microparticles and thereafter the microparticle
`product is obtained.
`One variable that affects the in vitro and in vivo perfor- 25
`mance of the microparticle product is the molecular weight
`of the polymer or polymeric matrix material in the final
`microparticle product. Molecular weight affects drug release
`characteristics. The molecular weight of a polymer influ(cid:173)
`ences the biodegradation rate of the polymer. For a diffu- 30
`sional mechanism of active agent release, the polymer
`should remain intact until all of the active agent is released
`from the microparticles, and then degrade. The active agent
`can also be released from the microparticles as the poly(cid:173)
`meric matrix material bioerodes. By an appropriate selection
`of polymeric materials a microparticle formulation can be
`made in which the resulting microparticles exhibit both
`diffusional release and biodegradation release properties.
`This is useful in affording multiphasic release patterns.
`It has been reported that the molecular weight of the 40
`poly(D,L-lactide) ("DL-PL") component of microcapsules
`containing up to 50% thioridazine free base decreased
`during fabrication, and in dissolution rate studies of the
`microcapsule (see Maulding, H.V. et al., Biodegradable
`Microcapsules: "Acceleration of Polymeric Excipient 45
`Hydrolytic Rate by Incorporation of a Basic Medicament",
`Journal of Controlled Release, Volume 3, 1986, pages
`103-117; hereinafter "the Maulding article"). The results
`reported in the Maulding article reveal that the degradation
`rate of DL-PL in ketotifen free base microcapsules was
`greater when the encapsulation process was carried out at 4°
`C. than it was when the encapsulation process was carried
`out at 25° C. In contrast, the degradation rate of DL-PL in
`thioridazine free base microcapsules was greater when the
`encapsulation process was carried out at 23° C. than it was
`when the encapsulation process is carried out at 4° C. Based
`on these results, the Maulding article suggests circumvent(cid:173)
`ing the polymer degradation by carrying out the preparation
`of microcapsules at 4 ° C. in the case of thioridazine base.
`The Maulding article does not provide a method by which
`the molecular weight of the polymer in the finished micro(cid:173)
`particle can be conveniently controlled. Nor does the Maul(cid:173)
`ding article provide a method for preparing microparticles
`that have a selected polymer molecular weight in the fin(cid:173)
`ished microparticle product.
`Thus, there is a need in the art for an improved method for
`preparing microparticles that controls the molecular weight
`
`35
`
`10
`
`SUMMARY OF THE INVENTION
`The present invention relates to a method for preparing
`microparticles. The present invention allows microparticle
`products of varying polymer molecular weights to be pro(cid:173)
`duced using the same molecular weight starting material.
`The present invention also allows microparticle products
`15 with substantially the same polymer molecular weight to be
`produced from starting materials of varying molecular
`weight. In one aspect of the invention, a method of preparing
`microparticles having a selected microparticle polymer
`molecular weight is provided. The method comprises:
`( a) preparing a first phase, the first phase comprising a
`nucleophilic compound, a polymer having a starting
`molecular weight, and a solvent for the polymer;
`(b) combining the first phase with a second phase under
`the influence of mixing means to form an emulsion;
`(c) combining the emulsion and an extraction medium,
`thereby forming microparticles; and
`( d) maintaining the first phase at a hold temperature for a
`hold period prior to step (b ), the hold period of suffi(cid:173)
`cient duration to allow the starting molecular weight of
`the polymer to reduce so that the selected microparticle
`polymer molecular weight is achieved.
`In a further aspect of the present invention, another
`method for preparing microparticles is provided. The
`method comprises:
`(a) providing a polymer having a starting molecular
`weight;
`(b) dissolving the polymer and a nucleophilic compound
`in a solvent to form a first phase;
`(c) combining the first phase with a second phase under
`the influence of mixing means to form an emulsion;
`( d) combining the emulsion and an extraction medium,
`thereby forming microparticles; and
`( e) maintaining the first phase at a hold temperature for a
`hold period prior to step ( c ), wherein the hold period is
`selected so that the starting molecular weight reduces
`so that a selected microparticle polymer molecular
`weight is achieved.
`In other aspects of the present invention, the foregoing
`50 methods comprise adding an active agent to the first phase.
`In yet further aspects of the present invention, the foregoing
`methods comprise adding an inactive agent to the first phase.
`In further aspects of the invention, the hold temperature is
`increased, thereby increasing the molecular weight decay of
`55 the polymer to reduce the duration of the hold period. The
`hold temperature can be decreased, thereby decreasing the
`molecular weight decay of the polymer to increase the
`duration of the hold period.
`Other aspects of the present invention include a microen-
`60 capsulated active agent and microparticles prepared by the
`methods of the present invention.
`Features and Advantages
`It is a feature of the present invention that it can be used
`to prepare microparticles, including microparticles contain-
`65 ing an active agent.
`It is a further feature of the present invention that it allows
`the hold time and temperature of a nucleophilic compound/
`
`

`

`US 6,264,987 Bl
`
`3
`polymer solution to be modified to achieve a selected
`polymer molecular weight in the microparticle product.
`An advantage of the present invention is that a selected
`~olymer molecular weight can be achieved in the micropar(cid:173)
`ticle product by using a variety of polymers, having varying 5
`starting molecular weights, by varying the hold time of the
`nucleophilic compound/polymer solution.
`A further advantage of the present invention is that
`microparticle products of varying polymer molecular
`weights can be produced using the same starting polymer, or 10
`using a polymer having the same starting molecular weight.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`The present invention is described with reference to the
`accompanying drawings. In the drawings, like reference
`numbers indicate identical or functionally similar elements.
`FIG. 1 depicts a graph of molecular weight loss percent(cid:173)
`age as a function of solution hold time (hours) at a 1 kg
`scale;
`FIG. 2 depicts a graph of molecular weight loss percent(cid:173)
`age as a function of solution hold time (hours) at a 20 kg
`scale;
`FIG. 3 depicts a graph of molecular weight (kD) as a
`function of solution hold time (hours) at 15° C., 25° C., and
`35° C.; and
`FIG. 4 shows one embodiment of an equipment configu(cid:173)
`ration suitable for preparing microparticles in accordance
`with the present invention.
`
`15
`
`w
`
`25
`
`30
`
`DETAILED DESCRIPTION OF THE DRAWINGS
`Overview
`The present invention provides an improved method for
`preparing microparticles. The methods of the present inven(cid:173)
`tion control the hold time and temperature of a polymer 35
`solution in order to control the molecular weight of the
`polymer in the finished microparticle product. In this
`manner, the methods of the present invention advanta(cid:173)
`geously allow a selected polymer molecular weight to be
`achieved from a variety of starting material molecular 40
`weights. Alternatively, microparticle products of varying
`polymer molecular weights can be produced using the same
`molecular weight starting material. Thus, a range of prod(cid:173)
`u~ts _can_be made from the same starting materials, thereby
`ehmmatmg the need to reformulate the finished product to 45
`achieve the desired molecular weight of the polymer in the
`finished product.
`The polymer solution used in the present invention com(cid:173)
`prises a nucleophilic compound. As used herein, "nucleo(cid:173)
`philic compound" refers to a compound that promotes by 50
`nucleo~hi~ic catalysis the ester hydrolysis, such as the poly(cid:173)
`mer sc1ss10n, that occurs in the biodegradation of biode(cid:173)
`gradable polymers, such as polymers comprising varying
`lacotide:glycolide ratios. Anucleophilic compound is a more
`effective nucleophile toward an ester group of the polymer 55
`than hydroxide ion or water. Nucleophilic compounds that
`catalyze the polymer hydrolysis include, but are not limited
`to, amines and carboxylate anions, and can be "active
`agents" (defined below) or "inactive agents" that are not
`active agents. Examples of nucleophilic compounds that are 60
`active agents include, but are not limited to, risperidone,
`9-hydroxyrisperidone, and pharmaceutically acceptable
`salts of the foregoing, naltrexone, and oxybutynin.
`Examples of nucleophilic compounds that are inactive
`agents include, but are not limited to, protamine sulfate, 65
`spermine, choline, ethanolamine, diethanolamine, and tri(cid:173)
`ethanolamine. It should be readily apparent to be one skilled
`
`4
`in the art that the present invention is not limited to any
`particular nucleophilic compound, and that the present
`invention encompasses other nucleophilic active agents and
`nucleophilic inactive agents.
`To ensure clarity of the description that follows, the
`following definitions are provided. By "microparticles" or
`"microspheres" is meant particles that comprise a polymer
`that serves as a matrix or binder of the particle. The
`microparticle may contain an active agent or other substance
`dispersed or dissolved within the polymeric matrix. The
`polymer is preferably biodegradable and biocompatible. By
`"bi~degradable" is meant a material that should degrade by
`bodily processes to products readily disposable by the body
`and should not accumulate in the body. The products of the
`biodegradation should also be biocompatible with the body.
`By "biocompatible" is meant not toxic to the body, is
`pharmaceutically acceptable, is not carcinogenic, and does
`not significantly induce inflammation in body tissues. As
`used herein, "body" preferably refers to the human body but
`,
`it should be understood that body can also refer to a
`non-human animal body. By "weight %" or "% by weight"
`is meant parts by weight per total weight of microparticle.
`For example, 10 wt. % active agent would mean 10 parts
`active agent by weight and 90 parts polymer by weight. By
`"controlled release microparticle" or "sustained release
`microparticle" is meant a microparticle from which an active
`agent or other type of substance is released as a function of
`time. By "mass median diameter" is meant the diameter at
`"'.hich half of the distribution (volume percent) has a larger
`diameter and half has a smaller diameter.
`By "active agent" is meant an agent, drug, compound,
`composition of matter or mixture thereof which provides
`some pharmacologic, often beneficial, effect. This includes
`foods, food supplements, nutrients, drugs, vitamins, and
`other beneficial agents. As used herein, the terms further
`include any physiologically and pharmacologically active
`substance that produces a localized or systemic effect in a
`patient. Such active agents include antibiotics, antiviral
`agents, anepileptics, analgesics, anti-asthmatics, anti(cid:173)
`inflammatory agents and bronchodilators, and may be inor(cid:173)
`ganic and organic compounds, including, without limitation,
`drugs which act on the peripheral nerves, adrenergic
`receptors, cholinergic receptors, the skeletal muscles the
`cardiovascular system, smooth muscles, the blood cir~ula(cid:173)
`tory system, synoptic sites, neuroeffector junctional sites,
`endocrine and hormone systems, the immunological system,
`the reproductive system, the skeletal system, autacoid
`systems, the alimentary and excretory systems, the hista(cid:173)
`mine system and the central nervous system. Suitable agents
`may be selected from, for example, polysaccharides,
`steroids, hypnotics and sedatives, tranquilizers,
`anticonvulsants, muscle relaxants, antiparkinson agents,
`analgesics, anti-inflammatories, muscle contractants,
`antimicrobials, antimalarials, hormonal agents including
`c~ntraceptives, sympathomimetics, polypeptides and pro(cid:173)
`terns capable of eliciting physiological effects, diuretics,
`lipid regulating agents, antiandrogenic agents, leukotriene
`antagonists, antiparasites, neoplastics, antineoplastics,
`hypoglycemics, nutritional agents and supplements, growth
`supplements, fats, ophthalmics, antienteritis agents, electro(cid:173)
`lytes and diagnostic agents.
`Method and Examples
`The following examples are provided to explain the
`invention, and to describe the materials and methods used in
`carrying out the invention. The examples are not intended to
`limit the invention in any manner.
`
`

`

`5
`Molecular Weight Experiments with Nucleophilic Com(cid:173)
`pounds
`
`6
`hold time (hours) of the active agent/polymer solution. The
`molecular weight of the polymer in the finished micropar-
`tide product was determined by GPC.
`
`US 6,264,987 Bl
`
`10
`
`EXAMPLE 1
`A series of experiments were conducted at the 1 kg scale 5
`that demonstrate the relationship between molecular weight
`of the finished microparticle product, and the duration of a
`hold period of a nucleophilic compound/polymer solution.
`Microparticles comprising risperidone were prepared at the
`one-kilogram scale. The 1 Kg process ( 400 grams of active
`agent and 600 grams of polymer) provides a theoretical drug
`loading of the microparticles of 40% ( 400 grams/1000
`gramsx100%).
`A 16.7 wt. % polymer solution was prepared by dissolv- 15
`ing 600 grams of MEDISORB® 7525 DL polymer
`(Alkermes, Inc., Blue Ash, Ohio) in ethyl acetate. A 24 wt.
`% drug solution was prepared by dissolving 400 grams of
`risperidone (basic nucleophilic active agent) (Janssen
`Pharmaceutica, Beerse, Belgium) in benzyl alcohol. A 20
`nucleophilic active agent/polymer solution ( organic phase)
`was prepared by mixing the drug solution into the polymer
`solution. The active agent/polymer solution was maintained
`at a temperature of 25±5° C. The active agent/polymer
`solution is held for a hold time of sufficient duration to 25
`achieve the selected or desired polymer molecular weight in
`the finished microparticle product, based on the starting
`molecular weight of the polymer. The results of the
`experiments, showing the effect of hold time on molecular
`weight loss, are discussed in more detail below with respect 30
`to Table 1 and FIG. 1.
`The second, continuous phase was prepared by preparing
`a 30 liter solution of 1 % polyvinyl alcohol (PVA), the PVA
`acting as an emulsifier. To this was added 2086 grams of
`ethyl acetate to form a 6.5 wt. % solution of ethyl acetate. 35
`The two phases were combined using a static mixer, such
`as a ½" Kenics static mixer available from Chemineer, Inc.,
`North Andover, Mass. A total flow rate of 3 L/min generally
`provides microparticle size distributions with a mass median
`diameter (MMD) in the range of about 80-90µ. The ratio of 40
`continuous phase to discontinuous phase was 5:1 (v/v).
`The quench liquid was 2.5% solution of ethyl acetate and
`water-for-injection (WFI) at 5-10° C. The volume of the
`quench liquid is 0.25L per gram of batch size. The quench
`step was carried out for a time period greater than about 4 45
`hours, with stirring of the microparticles in the quench tank.
`After completion of the quench step, the microparticles
`were collected, de-watered, and dried. The temperature was
`maintained at less than about 15° C.
`The microparticles were then re-slurried in a re-slurry
`tank using a 25% ethanol solution. The temperature in the
`re-slurry tank was in the range of about 0° C. to about 15°
`C. The microparticles were then transferred back to the
`quench tank for washing for a time period of at least 6 hours
`with another extraction medium (25% ethanol solution) that
`was maintained at preferably 25°±1 ° C.
`The microparticles were collected, de-watered, and dried.
`The temperature was warmed to greater than about 20° C.
`but below 40° C. Drying continued for a time period greater
`than about 16 hours.
`Twenty-four batches of risperidone microparticles at the 1
`kg scale were prepared using the process described above.
`Table 1 below shows, for each batch, the starting molecular
`weight of the polymer (kD), the final molecular weight of
`the polymer in the finished microparticle product (kD), the
`percent loss in molecular weight of the polymer, and the
`
`TABLE 1
`
`Batch#
`
`Starting Mw
`kD
`
`Final Mw
`kD
`
`% Loss
`
`Hold time
`Hours
`
`825
`708
`714
`812
`819
`319
`331
`423
`506
`512
`520
`527
`603
`610
`617
`902
`908
`921
`930
`915
`1021
`1028
`1110
`1215
`
`230
`161
`161
`161
`161
`131
`131
`131
`129
`129
`129
`129
`129
`129
`128
`128
`128
`128
`128
`92
`135
`138
`138
`138
`
`182
`110
`133
`100
`102
`110
`115
`78
`112
`86
`92
`95
`65
`101
`95
`85
`91
`99
`103
`69
`104
`119
`115
`111
`
`21.0
`32.0
`17.3
`37.9
`36.7
`16.2
`12.2
`40.7
`13.6
`33.7
`29.1
`26.8
`49.4
`22.0
`26.1
`33.8
`29.0
`23.2
`19.4
`24.8
`23.0
`13.7
`16.8
`19.4
`
`0.10
`2.08
`0.33
`2.40
`2.47
`0.10
`0.07
`2.85
`0.07
`3.10
`3.07
`2.22
`6.10
`1.13
`2.20
`1.90
`1.18
`0.08
`0.03
`1.82
`0.03
`0.45
`1.28
`1.50
`
`The data reported in Table 1 is depicted in the graph
`shown in FIG. 1. FIG. 1 shows an initial loss in molecular
`weight of approximately 17%, with an additional loss of
`approxamately 5.7% per hour of hold time of the active
`agent/polymer solution.
`EXAMPLE 2
`Additional experiments were conducted at the 20 kg scale
`that also demonstrate the relationship between molecular
`weight of the finished microparticle product, and the dura(cid:173)
`tion of a hold period of a nucleophilic compound/polymer
`solution. Microparticles comprising risperidone were pre(cid:173)
`pared at the twenty-kilogram scale. The 20 Kg process (8 kg
`of active agent and 12 kg of polymer) provides a theoretical
`drug loading of the microparticles of 40% (8 kg/20
`kgx100%).
`A 16.7 wt. % polymer solution was prepared by dissolv-
`ing 12 kg of MEDISORB® 7525 DL polymer (Alkermes,
`Inc., Blue Ash, Ohio) in ethyl acetate. A 24 wt. % drug
`solution was prepared by dissolving 8 kg of risperidone
`(Janssen Pharmaceutica, Beerse, Belgium) in benzyl alco-
`50 hol. A nucleophilic active agent/polymer solution ( organic
`phase) was prepared by mixing the drug solution into the
`polymer solution. The active agent/polymer solution was
`maintained at a temperature of 25±5° C. The active agent/
`polymer solution is held for a hold time of sufficient duration
`55 to achieve the selected or desired polymer molecular weight
`in the finished microparticle product, based on the starting
`molecular weight of the polymer. The results of the
`experiments, showing the effect of hold time on molecular
`weight loss, are discussed in more detail below with respect
`60 to Table 2 and FIG. 2.
`The second, continuous phase was prepared by preparing
`a 600 liter solution of 1 % PVA, the PVA acting as an
`emulsifier. To this was added 42 kg of ethyl acetate to form
`a 6.5 wt. % solution of ethyl acetate. The two phases were
`65 combined using a static mixer, such as a 1" Kenics static
`mixer available from Chemineer, Inc., North Andover,
`Mass.
`
`

`

`7
`The quench liquid was 2.5% solution of ethyl acetate and
`water-for-injection (WFI) at 5-10° C. The volume of the
`quench liquid is 0.25L per gram of batch size. The quench
`step was carried out for a time period greater than about 4
`hours, with stirring of the microparticles in the quench tank.
`After completion of the quench step, the microparticles
`were collected, de-watered, and dried. The temperature was
`maintained at less than about 15° C.
`The microparticles were then re-slurried in a re-slurry
`tank using a 25% ethanol solution. The temperature in the
`re-slurry tank was in the range of about 0° C. to about 15%
`microparticles were then transferred back to the quench tank
`for washing for a time period of at least 6 hours with another
`extraction medium (25% ethanol solution) that was main(cid:173)
`tained at preferably 25°±1 ° C.
`The microparticles were collected, de-watered, and dried.
`The temperature was greater than about 20° C. but below
`40° C. Drying continued for a time period about 16 hours.
`Four batches of risperidone microparticles at the 20 kg
`scale were prepared using the process described above.
`Table 2 below shows, for each batch, the starting molecular
`wieght of the polymer (kD), the final molecular weight of
`the polymer in the finished microparticle product (kD), the
`percent loss in molecular weight of the polymer, and the
`hold time hours) of the active agent/polymer solution. The
`molecular weight of the polymer in the finished micropar(cid:173)
`ticle product was determined by GPC.
`
`TABLE 2
`
`Batch#
`
`3308
`4068
`4138
`4208
`
`Starting Mw
`kD
`
`Final Mw
`kD
`
`% Loss
`
`Hold time
`hours
`
`146
`145
`143
`143
`
`117
`103
`111
`110
`
`20
`29
`22
`23
`
`0.5
`1.75
`1.0
`1.0
`
`The data reported in Table 2 show that from a relatively
`constant molecular wieght starting material (143 kD, 145
`kD, and 146 kD), a variable finished microparticle product
`molecular weight was achieved by varying the hold time of
`the active agent/polymer solution hold time. The data
`reported in Table 2 is depicted in the graph shown in FIG.
`2. FIG. 2 shows an initial loss in molecular weight of
`approximately 16%, with an additional loss of approxi(cid:173)
`mately 7.3% per hour of hold time of the active agent/
`polymer solution.
`
`EXAMPLE 3
`
`US 6,264,987 Bl
`
`8
`ing from 30%-75%. The ambient polymer and drug solu(cid:173)
`tions were mixed together until a single homogeneous
`solution ( organic phase) was produced. The aqueous phase
`was at ambient conditions and contained 1 % w/w polyvinyl
`5 alcohol and a saturating amount of ethyl acetate. These two
`solutions were pumped via positive displacement pumps at
`a ratio of 3:1 (aqueous:organic) through a¼" in-line mixer
`to form an emulsion. The emulsion was transferred to a
`stirring solvent extraction solution consisting of 2.5% w/w
`10 of ethyl acetate dissolved in distilled water at 5-10° C. and
`at a volume of 0.SL of extraction solution per theoretical
`gram of microparticles. Both the polymer and drug solvents
`were extracted into the extraction solution from the emul(cid:173)
`sion droplets to produce microparticles. The initial extrac-
`15 tion process ranged from two to four hours. The micropar(cid:173)
`ticles were collected on a 25 µm sieve and rinsed with a cold
`( <5° C.) 25% w/w ethanol solution. The microparticles were
`dried cold overnight ( approximately 17 hours) using nitro(cid:173)
`gen. The microparticles were then transferred to the reslurry
`20 solution, which consisted of a vigorously stirring 25% w/w
`ethanol solution at 5-10° C. After a short mixing time (five
`to fiffteen minutes), the reslurry solution and the micropar(cid:173)
`ticles were transferred to a stirring 25% w/w ethanol sec(cid:173)
`ondary extraction solution ( approximately 25° C. at a vol-
`25 ume of 0.2 L of secondary extraction solution per theoretical
`gram of microparticles ). The microparticles stirred for six
`hours enabling additional solvent removal from the micro(cid:173)
`particles to take place. The microparticles were then col(cid:173)
`lected on a 25 µm sieve and rinsed with a 25% w/w ethanol
`30 solution at ambient temperature. These microparticles dried
`in a hood under ambient conditions overnight
`(approximately 17 hours), were sieved to remove agglom(cid:173)
`erated microparticles and then placed into a freezer for
`storage.
`As shown below in Table 3, three batches of micropar-
`ticles were prepared using the 75:25 polymer, two batches
`for the 85:15 polymer, and four batches for the 65:35
`polymer. For each batch, Table 3 shows the starting molecu(cid:173)
`lar weight of the polymer (kD), and the final molecular
`40 weight of the polymer in the finished microparticle products
`(kD), and the percent loss in molecular weight of the
`polymer. The molecular weight of the polymer in the fin(cid:173)
`ished microparticle product was determined by GPC. The
`data in Table 3 provides an example of the loss in molecular
`45 weight of the polymer in a finished microparticle product
`containing a nucleophilic compound (naltrexone) for poly(cid:173)
`mers having varying lactide:glycolide ratios.
`
`35
`
`50
`
`55
`
`The starting molecular weight of the polymer (kD) and
`the final molecular weight of the polymer in a finished
`microparticle product (kD) was determined for micropar(cid:173)
`ticles containing the nucleophilic compound naltrexone. The
`starting polymer lactide:glycolide ratio was 75:25, 85:15,
`and 65:35. The polymers used were MEDISORB® 7525 DL
`polymer, MEDISORB® 8515 DL polymer and MEDIS(cid:173)
`ORB® 6535 DL polymer, all available from Alkermes, Inc.,
`Blue Ash, Ohio.
`The naltrexone base microparticles were produced using 60
`a co-solvent extraction process. The theoretical batch size
`was 15 to 20 grams. The polymer was dissolved in ethyl
`acetate to produce a 16.7% w/w polymer solution. The
`naltrexone base anhydrous was dissolved in benzyl alcohol
`to produce a 30.0% w/w solution. In various batches, the 65
`amount of drug and polymer used was varied to produce
`microparticles with different theoretical drug loading rang-
`
`TABLE 3
`
`Starting Polymer
`Lactide:glycolide ratio Batch
`
`Starting Mw Final Mw
`kD
`kD
`
`% Loss
`
`75:25
`
`85:15
`
`65:35
`
`99-123-004
`99-123-009
`99-123-012
`99-123-016
`99-123-024
`99-123-021
`99-123-028
`99-123-037
`99-123-034
`
`116.2
`116.2
`116.2
`109.7
`109.7
`102.3
`102.3
`102.3
`102.3
`
`76.0
`74.0
`74.3
`83.7
`74.9
`56.3
`63.4
`69.6
`79.6
`
`34.6
`36.3
`36.1
`23.7
`31.7
`45.0
`38.0
`32.0
`22.2
`
`EXAMPLE 4
`Additional experiments were conducted with other poly(cid:173)
`mers that also demonstrate the relationship between molecu(cid:173)
`lar weight of the finished microparticle product, and the
`duration of a hold period of a nucleophilic compound/
`
`

`

`US 6,264,987 Bl
`
`10
`be seen in Table 5, the longer the exposure or hold time of
`the drug/polymer solution, the lower the molecular weight
`of the polymer.
`
`TABLE 5
`
`9
`polymer solution. Microparticles comprising other polymers
`having different lactide:glycolide ratios were prepared.
`Microparticles comprising risperidone using polymers hav(cid:173)
`ing lactide:glycolide ratios of 65:35, 85:15, and 100:0 were
`prepared at the 1 Kg scale using the same process described 5
`above in Example 1. The polymers used were MEDIS(cid:173)
`ORB® 6535 DL polymer, MEDISORB® 8515 DL polymer,
`and MEDISORB® 100 DL polymer, all available from
`Alkermes, Inc., Blue Ash, Ohio.
`Table 4 below shows, for each polymer, the starting
`molecular weight of the polymer (kD), the final molecular
`weight of the polymer in the finished microparticle product
`(kD), the percent loss in molecular weight of the polymer,
`and the hold time (hours) of the active agent/polymer
`solution. The molecular weight of the polymer in the fin(cid:173)
`ished microparticle product was determined by GPC.
`
`Starting
`Polymer
`Lactide:
`glycolide
`10 ratio
`
`Starting
`Mw