(12) United States Patent
`Kohn et al.
`
`I 1111111111111111 11111 111111111111111 IIIII IIIII IIIII IIIII 1111111111 11111111
`US006455526Bl
`US 6,455,526 Bl
`Sep.24,2002
`
`(10) Patent No.:
`(45) Date of Patent:
`
`(54) BIODEGRADABLE POLYMER
`ENCAPSULATED PHARMACEUTICAL
`COMPOSITIONS AND METHOD FOR
`PREPARING THE SAME
`
`FOREIGN PATENT DOCUMENTS
`* 12/1991
`
`9118602
`
`WO
`
`OTHER PUBLICATIONS
`
`(75)
`
`Inventors: Rachel S. Kohn, Springfield, NJ (US);
`Stephen J. Hanley, Lebanon, NJ (US);
`Stephen J. Comiskey, Doylestown, PA
`(US)
`
`(73) Assignee: Aventis Pharmaceuticals, Inc.,
`Bridgewater, NJ (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by O days.
`
`(21) Appl. No.: 09/454,555
`
`(22) Filed:
`
`Dec. 7, 1999
`
`Related U.S. Application Data
`( 60) Provisional application No. 60/155,257, filed on Dec. 16,
`1998.
`
`Int. Cl.7 ....................... A61K 31/495; A61K 31/50
`(51)
`(52) U.S. Cl. ....................................................... 514/248
`(58) Field of Search ........................... 424/426; 514/248
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,389,330 A
`4,801,460 A
`5,134,122 A
`5,225,205 A
`5,360,610 A
`5,439,688 A
`5,456,917 A
`5,456,923 A
`5,505,963 A
`6,239,143 Bl *
`6,277,864 Bl *
`
`6/1983
`1/1989
`7/1992
`7/1993
`11/1994
`8/1995
`10/1995
`10/1995
`4/1996
`5/2001
`8/2001
`
`Tice et al.
`Goetz et al.
`Orsini
`Orsini
`Tice et al.
`Orsolini et al.
`Wise et al.
`Nakamichi et al.
`Munch et al.
`Cain et al. .................. 514/307
`Mondadori et al. ......... 514/317
`
`Journal of Controlled Release; 28 (1994) pp 121-129;
`Hiroaki Okada et al. "Drug delivery using biodegradable
`microspheres".
`Pharmacy International; Dec. 1986; pp 316-318; J. Heller
`"Controlled drug release from monolithic bioerodible poly(cid:173)
`mer devices".
`
`* cited by examiner
`
`Primary Examiner-Alton Pryor
`(74) Attorney, Agent, or Firm---Balaram Gupta
`
`(57)
`
`ABSTRACT
`
`A new class of biodegradable pharmaceutical compositions
`useful as sustained release medicamentous compositions,
`including methods of making and methods of using these
`compositions, are described and claimed. The method of
`making these compositions include the steps of: a) dry
`mixing of a pharmaceutically active molecule with a bio(cid:173)
`degradable polymer; b) melt extruding the mixture to form
`a solid solution of the active molecule in the polymer; and
`c) pulverizing the solid solution to form microparticles such
`that they can be formed into injectable formulations. Pre(cid:173)
`ferred embodiments include pharmaceutical compositions of
`polylactide-co-glycolide and ( + )-a-(2,3-dimethoxyphenyl)(cid:173)
`l-[2-( 4-fluorophenyl)ethyl]-4-piperidinemethanol ( active
`ingredient) and a method for its formation. These compo(cid:173)
`sitions release the active ingredient at a steady rate over a
`period of days to weeks. The active ingredient antagonizes
`the effects of serotonin at the 5HT 2A receptor and are useful
`in treating various conditions such as, for example, psycho(cid:173)
`ses including schizophrenia, obsessive compulsive disorder,
`sleep disorder, depression, anorexia, anxiety, drug addiction
`and bipolar disorders.
`
`43 Claims, No Drawings
`
`APOTEX EXHIBIT 1066
`Apotex v. Alkermes
`IPR2025-00514
`
`

`

`US 6,455,526 Bl
`
`1
`BIODEGRADABLE POLYMER
`ENCAPSULATED PHARMACEUTICAL
`COMPOSITIONS AND METHOD FOR
`PREPARING THE SAME
`
`This application claims the priority of U.S. Provisional
`Application Ser. No. 60/155,257, filed Dec. 16, 1998.
`
`BACKGROUND OF THE INVENTION
`
`5
`
`2
`toxicological considerations it is not possible to make cer(cid:173)
`tain of these drug formulations using solvents. Particularly,
`there are a number of regulatory restrictions in disposing of
`the solvent and solid wastes produced during the manufac-
`ture of these drug formulations.
`In addition, there are many disadvantages to the solvent
`method of producing microparticle drug formulations. First,
`this method is uneconomical for an industrial size scale-up.
`Second, there are also quality concerns such as reproduc-
`10 ibility and consistency of the drug distribution in the poly(cid:173)
`mer matrix, thus causing serious regulatory compliance
`problems. Finally, the solvent method generally produces
`only the microspheres in powder form.
`To overcome some of the problems of the solvent method
`of producing microparticles, there are methods known in the
`art to melt extrude a solid mixture of drug molecules and a
`variety of polymeric binders. For example, U.S. Pat. No.
`5,439,688 describes a process for preparing a pharmaceuti(cid:173)
`cal composition for the sustained release of a drug molecule.
`However, all of the drug molecules described therein are
`synthetic or naturally occurring peptides. U.S. Pat. No.
`5,456,923 describes a process for producing a solid disper(cid:173)
`sion of a drug dissolved or dispersed in a polymer or a
`diluent using a twin screw extruder. However, none of these
`25 prior art references teaches a formation of sustained release
`pharmaceutical compositions using a melt extrusion process
`wherein such compositions are suitable for the treatment of
`any of the CNS diseases described hereinabove.
`Furthermore, none of the prior art references describes a
`30 method for the formation of microparticles wherein the drug
`molecules are dissolved in the polymeric matrix and are
`useful in forming injectable formulations for the treatment
`of CNS related diseases.
`The following references are disclosed as background.
`U.S. Pat. No. 4,389,330 describes a microencapsulation
`process for the formation of microcapsules laden with an
`active agent involving a series of steps using a solvent.
`U.S. Pat. No. 4,801,460 describes a process for the
`preparation of solid pharmaceutical forms by an injection
`molding or an extrusion process.
`U.S. Pat. No. 5,360,610 describes polymeric micro(cid:173)
`spheres as injectable, drug-delivery systems for use to
`deliver bioactive agents to sites within the central nervous
`45 system.
`U.S. Pat. No. 5,439,688 and references cited therein
`describe processes for preparing pharmaceutical composi(cid:173)
`tions for the sustained and/or controlled release of a drug
`using a biodegradable polymer and incorporating as the
`50 active substance the salts of a natural or synthetic peptide.
`U.S. Pat. No. 5,456,917 describes a method for making an
`implantable bioerodible material for the sustained release of
`a medicament.
`U.S. Pat. No. 5,456,923 describes a method of manufac(cid:173)
`turing solid dispersion in which a drug is dissolved or
`dispersed in a polymer carrier or a diluent. The solid
`dispersions are formed in a twin screw extruder.
`U.S. Pat. No. 5,505,963 describes a method for making a
`60 pharmaceutical composition free of organic solvents useful
`for oral administration. The method employs a solidified
`granulates of an active ingredient in admixture with a
`meltable auxiliary substance which is soluble in the active
`ingredient at elevated temperatures.
`J. Controlled Release, 28 (1994) 121-129 describes a
`review of drug delivery systems using various kinds of
`biodegradable polymers.
`
`1. Field of the Invention
`This invention relates to methods for the production of
`sustained release compositions containing a biodegradable
`polymer and a pharmaceutically active molecule, which are
`useful in the treatment of a variety of diseases, including
`certain psychoses such as, for example, schizophrenia, 15
`obsessive compulsive disorder, anxiety, and bipolar disor(cid:173)
`ders. More specifically, the present invention relates to
`sustained release compositions of a biodegradable polyester
`and a pharmaceutically active molecule capable of exerting
`serotonin receptor antagonist activity at the 5HT 2 receptor, 20
`method of making the same, and method of treating patients
`in need of such compositions.
`2. Description of the Prior Art
`It has long been appreciated that the continuous release of
`certain drugs over an extended period following a single
`administration could have significant practical advantages in
`clinical practice. It is also well recognized in the art that
`delivering a drug to its therapeutic site of action, such as, for
`example, the central nervous system (CNS) can be a very
`difficult task because of the numerous chemical and physical
`barriers which must be overcome in order for such delivery
`to be successful. A particularly difficult problem is in long
`term administration of a drug to patients suffering from CNS
`related diseases. This is particularly true for patients suffer- 35
`ing from various CNS related diseases, such as
`schizophrenia, obsessive compulsive disorders, sleep
`disorders, depression, anxiety, anorexia and drug addiction.
`In addition, there is a need to maintain a steady drug level
`in patients suffering with these diseases so as to provide an 40
`improved efficacy in treatment with lower peak drug con-
`centrations.
`As a result, many methods have been developed to deliver
`drugs to the CNS effectively. One such method involves
`preparation of sustained release formulations. The sustained
`release formulations may however be of various different
`types. For example, a drug may be chemically modified into
`a form called a prodrug, that is capable of transforming into
`its active form slowly, either before or after crossing the
`blood-brain barrier. An example of such a prodrug delivery
`system consists of the neurotransmitter dopamine attached
`to a molecular mask derived from the fat-soluble vitamin
`niacin. The modified dopamine is taken up into the brain
`where it is then slowly stripped from its prodrug mask to
`yield free dopamine.
`Other common methods used to prepare sustained release
`formulations include formation of microparticles in which
`bioactive agents are contained within a compatible biode(cid:173)
`gradable polymer. A number of methods are reported in the
`art, which use a wide range of organic solvents to prepare
`such microparticles. For example, U.S. Pat. No. 4,389,330
`describes a method of forming microcapsules by dissolving
`or dispersing an active agent along with a wall forming
`material in a solvent. Common solvents used for the forma(cid:173)
`tion of such microcapsules include chlorinated 65
`hydrocarbons, particularly, methylene chloride, acetone,
`alcohols, and the like. However, due to environmental and
`
`55
`
`

`

`US 6,455,526 Bl
`
`3
`Pharmacy International, (1986), 7 (12), 316-18, describes
`a review of controlled drug release from monolithic bio(cid:173)
`erodible polymer devices.
`All of the references cited herein are incorporated herein
`by reference in their entirety.
`
`SUMMARY OF THE INVENTION
`Accordingly, it is an object of the present invention to
`provide a melt extrusion method for the formation of micro(cid:173)
`particles in which the drug molecules are substantially
`dissolved in the polymer matrix forming a solid solution. It
`is further an object of the present invention to provide
`microparticles capable of releasing the drug molecules at a
`sustained release rate over an extended period of time.
`Finally, it is also an object of the present invention to provide 15
`injectable microparticle formulations for the treatment of
`various CNS diseases including diseases or conditions treat(cid:173)
`able by antagonizing the effects of serotonin at the 5HT 2
`receptor, such as schizophrenia, obsessive compulsive
`disorders, sleep disorders, depression, anxiety, anorexia and 20
`drug addiction.
`Surprisingly, it has now been found that solid solution of
`a biodegradable polymer and a pharmaceutically active
`molecule can be made by a melt extrusion process. Some of
`the advantages gained by the practice of the method of the 25
`present invention, individually and/or in combinations, are:
`a) the pharmaceutically active compound is essentially dis(cid:173)
`solved in the biodegradable polymer matrix forming a solid
`solution; b) the compositions of the present invention can be
`readily formed into microparticles; and c) the compositions 30
`of the present invention can be formulated into injectable
`formulations for the sustained release of the active com(cid:173)
`pound. Advantageously, the compositions of the present
`invention are useful in the treatment of various CNS dis-
`eases.
`Thus, in accordance with the practice of the present
`invention there is provided a method for the production of a
`pharmaceutical composition comprising the steps of:
`a) mixing a suitable amount of pharmaceutically active 40
`molecule capable of exerting serotonin receptor
`antagonist activity with a suitable amount of biode(cid:173)
`gradable polymer for a sufficient period of time and at
`suitable temperature and pressure conditions to form a
`dry mixture of said pharmaceutically active molecule 45
`and said polymer, wherein said biodegradable polymer
`has a glass transition temperature (T g) of less than
`about 60° C.;
`b) subjecting said dry mixture to a suitable shear mixing
`under suitable temperature and pressure conditions for 50
`a sufficient period of time such that said polymer
`softens to form a fluidized medium and said pharma(cid:173)
`ceutically active molecule is sufficiently, dissolved to
`form a solid solution having substantially homoge(cid:173)
`neously dispersed mixture of said pharmaceutically 55
`active molecule and said polymer, and said homoge(cid:173)
`neous mixture is formed into a strand;
`c) pelletizing said strand; and
`d) pulverizing said pellets to form sustained release
`microparticles of the biodegradable polymer and the 60
`pharmaceutical composition, wherein the micropar(cid:173)
`ticles are having a size distribution in the range of from
`about 10 to 200 µm such that the microparticles are
`suitable for forming an injectable formulation.
`In one of the preferred embodiments, a biodegradable 65
`polyester is used as the matrix polymer to dissolve a
`pharmaceutically active molecule capable of exerting sero-
`
`4
`tonin receptor antagonist activity. In this preferred
`embodiment, the sustained release microparticles are formed
`in a twin screw extruder. In a more preferred embodiment of
`this invention, the twin screw extruder is made up of at least
`5 one left handed element and the extrusion is carried out at a
`preferred temperature range of from about 95° C. to about
`115° C.
`In another preferred embodiment, a solid solution is
`formed using a polylactide-co-glycolide polymer (PLGA)
`10 and a pharmaceutically active compound of Formula I or
`pharmaceutically acceptable salts thereof. In this preferred
`embodiment, the dry blend of PLGA polymer and com(cid:173)
`pound I was dried in a vacuum oven at a temperature of
`about 25° C.
`
`Formula I
`
`As such that the moisture content of the dry blend is less than
`about 0.02 weight percent. The melt extrusion of the dry
`blend was carried out in a twin screw extruder equipped with
`at least one left handed element to form a homogeneous
`mixture in which compound I is substantially dissolved in
`the PLGA matrix. In this preferred embodiment, pelletizing,
`pulverizing and sieving of the melt extruded blend affords
`microparticles having the size distribution of from about 10
`35 to 100 µm, which are suitable for forming injectable formu(cid:173)
`lations.
`In another aspect of this invention, there is also provided
`a pharmaceutical composition for the sustained release of a
`medicamentous substance comprising microparticles having
`a size distribution in the range of from about 10 to 100 µm
`formed of:
`a) a biodegradable polymer in an amount of about 80 to
`95 percent by weight, wherein said polymer has a glass
`transition temperature (Tg) of less than about 60° C.;
`and
`b) a pharmaceutically active compound of Formula I or a
`pharmaceutically acceptable salt thereof in an amount
`of about 5 to 20 percent by weight;
`
`Formula I
`
`wherein said compound is substantially dissolved and uni(cid:173)
`formly dispersed in said polymer.
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`As used herein the following terms shall have the
`assigned meanings and/or definitions:
`
`

`

`US 6,455,526 Bl
`
`5
`
`5
`"Biodegradable", "bioabsorbable", "bioresorbable" or
`"bioerodible" polymer shall mean any polymeric material
`capable of undergoing a degradation process in a biological
`environment, such as consumption by a human body and is
`converted to products that can be readily eliminated from the
`body.
`"Drug", "medicament", "pharmaceutically active" or
`"therapeutically active" shall mean any organic compound
`or substance having bioactivity and adapted or used for a
`therapeutic purpose.
`"Microparticles", "microspheres" or "microcapsules"
`shall mean any free flowing powder consisting substantially
`of spherical particles of 500 microns or less in diameter,
`usually 200 microns or less in diameter.
`"Monolithic" shall mean a composition in which the
`active agent is substantially homogeneously dispersed
`throughout an essentially therapeutically inert matrix.
`"Patient" means a warm blooded animal, such as for
`example rat, mice, dogs, cats, guinea pigs, and primates such
`as humans.
`The term "pharmaceutically acceptable salt" refers to
`those salts that are not substantially toxic at the dosage
`administered to achieve the desired effect and do not inde(cid:173)
`pendently possess significant pharmacological activity. The
`salts included within the scope of this term are
`hydrobromide, hydrochloride, sulfuric, phosphoric, nitric,
`formic, acetic, propionic, succinic, glycolic, lactic, malic,
`tartaric, citric, ascorbic, a-ketoglutaric, glutamic, aspartic,
`maleic, hydroxymaleic, pyruvic, phenylacetic, benzoic,
`p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic,
`hydro xye thanes ulfo nic,
`e th yle ne sulfa nic,
`halobenzenesulfonic, toluenesulfonic, naphthalenesulfonic,
`methanesulfonic, sulfanilic, and the like.
`"Pharmaceutically acceptable carrier" is a solvent,
`dispersant, excipient, adjuvant or other material having
`acceptable toxicity, which is mixed with the composition of
`the present invention in order to permit the formation of a
`pharmaceutical composition, i.e., a dosage form capable of
`administration to the patient. One example of such a carrier
`is a pharmaceutically acceptable oil typically used for
`parenteral administration.
`"Solid solution" means that the pharmaceutically active
`molecule is substantially dissolved in the polymer to form a
`single phase system.
`"Sustained release" means that a composition when
`administered to a patient is capable of releasing the active
`molecule at a steady rate for a period of at least 2 weeks,
`preferably for a period of about 2 weeks to one month or for
`longer periods if needed.
`"Therapeutically effective amount" means an amount of
`the compound which is effective in treating the named
`disorder or condition.
`"Treat" or "treating" means to alleviate symptoms, elimi(cid:173)
`nate the cause of the symptom either on a temporary or
`permanent basis, or to prevent or slow the appearance of
`symptoms of the named disorder or condition.
`One of the advantages of the present method of the
`invention is that the microparticles of well defined size
`distribution can be obtained in which the pharmaceutically
`active molecule is dissolved in the biodegradable polymer
`matrix forming a solid solution. This is achieved by a
`scalable melt extrusion process, thus avoiding the use of
`undesirable solvents as used by the conventional processes. 65
`Thus, the method of the present invention not only offers
`environmental benefits (i.e., avoids disposal of the solvents)
`
`6
`but also provides an economical way of making sustained
`release drug formulations. Another important advantage of
`the method of the present invention is that the well defined
`microparticles of narrow; size distribution can be made by
`the practice of this invention, which are useful for forming
`a variety of injectable formulations. Yet another advantage
`gained by the practice of this invention is that solid solution
`of a biodegradable polymer and a pharmaceutically active
`molecule can be readily made wherein the active molecule
`10 is a neuro-active, non-peptidic small molecule and may
`contain a reactive group such as hydroxy group.
`By judicious practice of the method of the present inven(cid:173)
`tion the microparticles formed are substantially free from
`any other reactive products of the pharmaceutically active
`15 molecule and the biodegradable polymer. Surprisingly, the
`method of the present invention offers pharmaceutical com(cid:173)
`positions in which the bioavailability of the pharmaceuti(cid:173)
`cally active molecule is enhanced because of the fact that the
`active molecule is substantially dissolved in the polymer
`20 matrix. Thus, the microparticles of the composition of the
`present invention are substantially "monolithic." That is, the
`active molecule is dispersed uniformly throughout the poly(cid:173)
`mer matrix. It should be noted that many of these features
`described herein are not readily attainable by most of the
`25 conventional methods, including solvent and other melt
`extrusion methods.
`In accordance with the practice of the present invention
`there is provided a method for the production of pharma(cid:173)
`ceutical compositions. In the method of the present
`30 invention, the first step involves mixing of a suitable amount
`of the pharmaceutically active molecule with a suitable
`amount of the biodegradable polymer for a sufficient period
`of time and at suitable temperature and pressure conditions
`to form a dry mixture.
`Mixing of the polymer and the pharmaceutically active
`molecule can be done at ambient atmospheric conditions,
`preferably in the temperature range of from about 20° C. to
`30° C. and at atmospheric pressure. The time required for
`40 mixing depends upon the quantities of the polymer and the
`active molecules used and may involve 30 minutes to 2
`hours or longer. The polymer and the pharmaceutically
`active molecule may be used as received from the commer(cid:173)
`cial sources, generally, in the form of powder or pellets.
`45 However, it has been observed that it is beneficial to grind
`the powder or pellets to form a well mixed dry mixture. Any
`of the grinding or milling techniques known in the art may
`be used for this purpose including cryogenic grinding or
`milling methods.
`It has also been observed that drying of the dry mixture of
`polymer and pharmaceutically active molecule is also ben(cid:173)
`eficial to remove any residual moisture in the polymer or the
`active molecule. Among several benefits, two key benefits of
`drying the dry mixture are: a) minimization of the degrada-
`55 tion of the polymer; and b) minimization of any potential
`reaction between the polymer and the pharmaceutically
`active molecule. Any of the drying techniques known in the
`art may be used. For example, drying the mixture under
`vacuum at about room temperature, i.e., 20 to 30° C. for a
`60 period of about 2 to 48 hours or longer provides desirable
`results.
`As stated hereinabove, a wide variety of non-peptidic
`pharmaceutically active molecules having a molecular
`weight less than about 600 may be used in this invention.
`The expression "non-peptidic" as used herein shall mean
`that the molecules which are not peptides, that is, molecules
`that are not formed by the reaction of two or more of the
`
`35
`
`50
`
`

`

`US 6,455,526 Bl
`
`8
`using any of the known methods in the art to form the
`microparticles of this invention, such as cryogenic milling as
`described herein. The microparticles so formed are sieved
`such that they exhibit a size distribution in the range of from
`about 10 to 200 µm, more preferably 10 to 100 µm. These
`microparticles are suitable for forming an injectable formu(cid:173)
`lation.
`As discussed hereinabove, preferred pharmaceutically
`active molecules for the practice of the method of present
`invention are neuro-active molecules or agents. Examples of
`neuro-active molecules or agents that may be microencap(cid:173)
`sulated and used according to the present invention are
`neurotransmitters and neurotrophic factors including such
`agents as norepinephrine, epinephrine, serotonin, dopamine,
`substance P, somatostatin, and agonists and antagonists of
`these active molecules or agents.
`Preferred pharmaceutically active molecules are those
`which are capable of exerting serotonin receptor antagonist
`activity. Particularly preferred pharmaceutically active mol(cid:173)
`ecules for the practice of the method of present invention are
`SHT 2A receptor antagonists. A most preferred pharmaceuti(cid:173)
`cally active molecule is ( +)-isomer of a-(2,3-
`dime tho xyphe ny 1 )-1 [ 2-( 4-fl uo rop hen y 1 )e thy 1 ]-4-
`piperidinemethanol, Compound of Formula I or a
`pharmaceutically acceptable salt thereof.
`
`Formula I
`
`OH
`
`OCH3
`
`10
`
`7
`naturally occurring amino acids. A wide variety of biode(cid:173)
`gradable polymers may be employed in this invention,
`however, biodegradable polymers having a glass transition
`temperature (T g) less than about 60° C. are particularly
`preferred. As used herein "glass transition temperature" 5
`refers to the softening temperature of the polymer, i.e., the
`transition temperature above which a noncrystalline poly(cid:173)
`mer has enough thermal energy for long segments of each
`polymer chain to move randomly. In other words, at a
`temperature higher than the glass transition temperature, the
`polymer molecules have enough motion to be mobile, and
`this is referred to herein as a "fluidized medium."
`In a second step of the method of the present invention the
`dry mixture as obtained in the first step is subjected to a
`suitable shear mixing at suitable temperature and pressure 15
`conditions for a sufficient period of time such that the
`polymer softens to form a fluidized medium. As used herein
`"shear mixing" means that mixing of the dry mixture at an
`elevated temperature, preferably above the glass transition
`temperature of the polymer, under shear using any of the 20
`methods known in the art. Preferably, shear mixing is carried
`out in a mixing bowl or an extrusion equipment as described
`herein. The conditions are maintained such that the phar(cid:173)
`maceutically active molecule is allowed to dissolve in the
`fluidized polymer medium and form substantially a homo- 25
`geneous mixture of the pharmaceutically active molecule
`and the polymer.
`To obtain best benefits from this invention, it is critical
`that the pharmaceutically active molecule is sufficiently
`miscible or dissolved in the polymer matrix, as mentioned 30
`hereinabove. To determine the extent of pharmaceutically
`active molecule dissolved in the polymer matrix, a variety of
`techniques well known in the art may be used depending
`upon the type of polymer and the active molecule employed.
`In general, differential scanning calorimetry (DSC) may be 35
`used to determine the level of active molecule dissolved in
`the polymer if the active molecule has a definitive melting
`point. From the heat of fusion determined from the melting
`point peak of the active molecule, it is possible to compute
`the extent of active molecule dissolved. Thus, as more active 40
`molecule dissolves in the polymer the size of the melting
`peak is reduced correspondingly. The melting peak is com(cid:173)
`pletely absent when all of the active molecule is dissolved in
`the polymer. In addition, the glass transition temperature
`(Tg) of the polymer decreases with increasing solubility of 45
`the active molecule. Other techniques, such as scanning
`electron microscopy (SEM) may also be used to determine
`the homogeneity of the pharmaceutical composition of the
`present invention. That is, the undissolved pharmaceutically
`active molecule will appear as a separate phase.
`In a third step of the method of the present invention, the
`fluidized mixture of the polymer and pharmaceutically
`active molecule is cooled to form a strand and pelletized. As
`used herein "pelletizing" refers to the formation of pellets
`from the strand formed according to this invention. Any of 55
`the well known methods in the art may be used to strand and
`pelletize the mixture of the polymer and pharmaceutically
`active molecule. For example, the molten fluid may by
`extruded into a strand by passing through an orifice. Then
`the strand is taken over a conveyor belt, which is being 60
`purged by dry nitrogen or air. The strand is finally fed into
`a pelletizer to form pellets.
`In a final step, the pellets from the third step are pulver(cid:173)
`ized to form sustained release microparticles of the biode(cid:173)
`gradable polymer and the pharmaceutically active molecule. 65
`As used herein "pulverizing" refers to conversion of pellets
`formed according to this invention to small particulate form
`
`Any of the known biodegradable polymer may be used
`under certain specific conditions as described herein. For
`instance, a polymer having a glass transition temperature
`lower than 60° C. may be employed in the formation of
`microparticles of the present invention, provided that the
`pharmaceutically active molecules of the present invention
`are dissolved sufficiently in such a polymer matrix by
`practicing the method of the present invention. It should
`further be noted that such biodegradable polymer is suitable
`as a raw material in the manufacture of pharmaceutical
`products and its function is not adversely affected by the
`shear mixing step (i.e., step b) of the method of the present
`50 invention. Examples of such polymers are polyesters,
`polyamides, polyanhydrides, polyorthoesters,
`polycarbonates, poly(phosphoesters), poly(phosphazenes),
`poly(iminocarbonates), and the like. It should be noted that
`a mixture containing one or more of these polymers may
`also be employed. Such polymers are easily prepared as
`described in the literature cited herein and they can be
`obtained commercially from specialized firms known to
`those of ordinary skill in the pertinent manufacturing art.
`Particularly preferred polymers suitable for the method of
`the present invention are polyesters. Specific examples of
`polyesters include polylactide, polyglycolide, polylactide(cid:173)
`co-glycolide, polyhydroxybutyrate, polycaprolactone,
`polytartarate, and the like. Two or more mixtures of these
`polymers may also be used. A particularly preferred poly-
`ester is polylactide-co-glycolide (PLGA).
`The PLGA polymer has a number of advantages which
`render it unique to the method of the present invention. An
`
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`US 6,455,526 Bl
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`9
`advantage of PLGA is that it is similar to materials used in
`the manufacture of present day bioabsorbable sutures.
`Another advantage is that this material is biocompatible with
`the tissue of the CNS. Still another advantage is that this
`material is biodegradable within the tissues of the CNS 5
`without producing any toxic byproducts of degradation.
`An important advantage of this material, as it relates to
`this invention, is the ability to modify the duration of drug
`release by manipulating the polymer's biodegradation
`kinetics, i.e., by modifying the ratio of lactide and glycolide 10
`in the polymer. This is particularly important because the
`ability to deliver neuro-active molecules at a controlled rate
`over a predetermined period of time is a more effective and
`desirable therapy over current procedures for administration.
`Microparticles made with this polymer serve two functions: 15
`they protect drugs from degradation and they release drugs
`at a controlled rate over a predesired time. As stated
`hereinabove, although polymers have been previously
`reported for use in the microencapsulation of drugs includ(cid:173)
`ing PLGA, the physical, chemical and medical parameters of
`the microencapsulating polymer for pharmaceutically active
`molecules to be used in accordance with the present inven(cid:173)
`tion are narrow. This is especially true for the formation of
`sustained release injectable pharmaceutical compositions for
`delivering to the CNS active drugs according to the present
`invention.
`For instance, the PLGA polymer that is suitable in the
`method of the present invention may have a wide range of
`average molecular weight provided that its glass transition
`temperature is less than 60° C. However, preferably, the
`average molecular weight of PLGA polymer is in the range
`of from about 20,000 to about 100,000, and is more pref(cid:173)
`erably between about 30,000 and 45,000. The PLGA poly(cid:173)
`mer further contains 45 to 90 mole percent of lactide and 10
`to 55 mole percent