U.S. patent application number 11/129434 was filed with the patent office on 2005-12-15 for preparation of biodegradable, biocompatible microparticles containing a biologically active agent.
This patent application is currently assigned to Alkermes Controlled Therapeutics Inc. II. Invention is credited to Lewis, Danny H., Ramstack, J. Michael, Rickey, Michael E..
Application Number | 20050276859 11/129434 |
Document ID | / |
Family ID | 21917114 |
Filed Date | 2005-12-15 |
United States Patent
Application |
20050276859 |
Kind Code |
A1 |
Rickey, Michael E. ; et
al. |
December 15, 2005 |
Preparation of biodegradable, biocompatible microparticles
containing a biologically active agent
Abstract
A method for preparing biodegradable, biocompatible
microparticles. A first phase is prepared that includes a
biodegradable, biocompatible polymer, an active agent, and a
solvent. A second phase is prepared. The first and second phases
are combined to form an emulsion in which the first phase is
discontinuous and the second phase is continuous. The discontinuous
first phase is separated from the continuous second phase. The
residual level of solvent in the discontinuous first phase is
reduced to less than about 2% by weight.
Inventors: |
Rickey, Michael E.;
(Loveland, OH) ; Ramstack, J. Michael; (Lunenburg,
MA) ; Lewis, Danny H.; (Hartselle, AL) |
Correspondence
Address: |
COVINGTON & BURLING
ATTN: PATENT DOCKETING
1201 PENNSYLVANIA AVENUE, N.W.
WASHINGTON
DC
20004-2401
US
|
Assignee: |
Alkermes Controlled Therapeutics
Inc. II
Cambridge
MA
|
Family ID: |
21917114 |
Appl. No.: |
11/129434 |
Filed: |
May 16, 2005 |
Related U.S. Patent Documents
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Application
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Filing Date |
Patent Number |
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11129434 |
May 16, 2005 |
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10626538 |
Jul 25, 2003 |
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10626538 |
Jul 25, 2003 |
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10278011 |
Oct 23, 2002 |
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10278011 |
Oct 23, 2002 |
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10120492 |
Apr 12, 2002 |
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10120492 |
Apr 12, 2002 |
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09920862 |
Aug 3, 2001 |
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6403114 |
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09920862 |
Aug 3, 2001 |
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09578717 |
May 26, 2000 |
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6290983 |
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09578717 |
May 26, 2000 |
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09263098 |
Mar 5, 1999 |
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6110503 |
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09263098 |
Mar 5, 1999 |
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09071865 |
May 4, 1998 |
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5916598 |
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09071865 |
May 4, 1998 |
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08850679 |
May 2, 1997 |
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5792477 |
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60041551 |
May 7, 1996 |
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Current U.S.
Class: |
424/489 ; 264/5;
514/259.41 |
Current CPC
Class: |
Y10T 428/2985 20150115;
A61K 9/1694 20130101; A61K 9/1647 20130101; B01J 13/04 20130101;
A61P 25/24 20180101; A61K 31/519 20130101; A61K 9/5089
20130101 |
Class at
Publication: |
424/489 ;
264/005; 514/259.41 |
International
Class: |
A61K 031/519; A61K
009/14; B29B 009/00 |
Claims
What is claimed is:
1. A method for preparing microparticles, comprising: (A) preparing
a first phase comprising a biodegradable and biocompatible polymer,
a psychotherapeutic agent, and a solvent; (B) preparing an aqueous
phase; (C) combining said first phase and said aqueous phase to
form an emulsion in which said first phase is discontinuous and
said aqueous phase is continuous; (D) separating said discontinuous
first phase from said continuous aqueous phase; and (E) reducing a
residual level of said solvent in said discontinuous first phase to
less than about 2% by weight.
2. The method of claim 1, wherein step (E) comprises: washing said
discontinuous first phase with an aqueous solution at a temperature
in the range of from about 25.degree. C. to about 40.degree. C.
3. The method of claim 1, wherein step (E) comprises: washing said
discontinuous first phase with an aqueous solvent system comprising
water and a second solvent for said solvent.
4. The method of claim 1, wherein said solvent is a solvent blend
of at least two mutually miscible organic solvents.
5. The method of claim 2, wherein said aqueous solution comprises
water and a C.sub.1-C.sub.4 alcohol.
6. The method of claim 5, wherein said C.sub.1-C.sub.4 alcohol is
ethanol.
7. The method of claim 2, wherein said aqueous solution is
water.
8. The method of claim 3, wherein said aqueous solvent system
further comprises a C.sub.1-C.sub.4 alcohol.
9. The method of claim 8, wherein said C.sub.1-C.sub.4 alcohol is
ethanol.
10. The method of claim 1, wherein step (C) is carried out using a
static mixer.
11. Microparticles prepared by the method of claim 1.
12. Microparticles prepared by the method of claim 1, wherein said
psychotherapeutic agent is selected from the group consisting of
risperidone, 9-hydroxyrisperidone, and pharmaceutically acceptable
salts of the foregoing.
13. Microparticles prepared by the method of claim 10.
14. The method of claim 10, wherein said psychotherapeutic agent is
selected from the group consisting of risperidone,
9-hydroxyrisperidone, and pharmaceutically acceptable salts of the
foregoing.
15. Microparticles prepared by the method of claim 14.
16. Microparticles prepared by the method of claim 1, wherein said
polymer is selected from the group consisting of poly(glycolic
acid), poly(d,l-lactic acid), poly(l-lactic acid), and copolymers
of the foregoing.
17. Microparticles prepared by the method of claim 12, wherein said
polymer is selected from the group consisting of poly(glycolic
acid), poly(d,l-lactic acid), poly(l-lactic acid), and copolymers
of the foregoing.
18. A method for preparing microparticles, comprising: combining an
organic phase and an aqueous phase in a static mixer to form an
emulsion, wherein said organic phase comprises a biodegradable and
biocompatible polymer, an active agent, and a solvent; separating
said organic phase from said aqueous phase; and washing said
organic phase with an ethanol wash to thereby reduce a residual
level of said solvent in said organic phase to less than about 2%
by weight.
19. Microparticles prepared by the method of claim 18.
20. Microparticles prepared by the method of claim 18, wherein said
active agent comprises a basic moiety.
21. Microparticles prepared by the method of claim 18, wherein said
solvent is free from halogenated hydrocarbons.
22. Microparticles prepared by the method of claim 18, wherein said
solvent is a blend of ethyl acetate and benzyl alcohol.
23. Microparticles prepared by the method of claim 18, wherein said
solvent comprises ethyl acetate.
24. Microparticles prepared by the method of claim 18, wherein said
ethanol wash is an aqueous solution of 25% ethanol.
25. Microparticles prepared by the method of claim 18, wherein said
polymer is selected from the group consisting of poly(glycolic
acid), poly(d,l-lactic acid), poly(l-lactic acid), and copolymers
of the foregoing.
Description
[0001] This application claims priority to provisional application
No. 60/041,551, filed May 7, 1996, the entirety of which is hereby
incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to microparticles having a reduced
level of residual solvent(s) and to a method for the preparation of
such microparticles. More particularly, the present invention
relates to pharmaceutical compositions comprising
controlled-release microparticles having improved shelf-life, said
microparticles comprising active agents encapsulated within a
polymeric matrix, and to a method for forming such
microparticles.
[0004] 2. Description of the Related Art
[0005] Compounds can be encapsulated in the form of microparticles
by a variety of known methods. 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 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 known mixing techniques, in a
solvent containing the wall-forming material. Solvent is then
removed from the microparticles and thereafter the microparticle
product is obtained.
[0006] An example of a conventional microencapsulation process is
disclosed in U.S. Pat. No. 3,737,337 wherein a solution of a wall
or shell forming 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.
[0007] Another example of a process in which solvent is removed
from microparticles containing a substance is disclosed in U.S.
Pat. 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.
[0008] In still another process, as disclosed in U.S. Pat. No.
3,691,090, organic solvent is evaporated from a dispersion of
microparticles in an aqueous medium, preferably under reduced
pressure.
[0009] Similarly, U.S. Pat. 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
miscibility 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.
[0010] Another example of a process in which an active agent may be
encapsulated is disclosed in U.S. Pat. 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.degree. 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.
[0011] Tice et al in U.S. Pat. No. 4,389,330 describe the
preparation of microparticles containing an active agent by using a
two-step solvent removal process. 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 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.
[0012] Tice et al., in U.S. Pat. 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.
[0013] 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.
[0014] Bodmeier, R., et al., International Journal of Pharmaceutics
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 liquid, such as
acetone, ethyl acetate, methanol, dimethylsulfoxide, chloroform, or
benzene to enhance drug content.
[0015] 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.
[0016] Kino et al., in WO 94/10982, disclose sustained-release
microspheres consisting of a hydrophobic antipsychotic agent
encapsulated in a biodegradable, biocompatible high polymer. The
antipsychotic may be fluphenazine, chlorpromazine, sulpiride,
carpipramine, clocapramine, mosapramine, risperidone, clozapine,
olanzapine, sertindole, or (pref.) haloperidol or bromperidol. The
biodegradable, biocompatible high polymer may be a fatty acid ester
(co)polymer, polyacrylic acid ester, polyhydroxylactic acid,
polyalkylene oxalate, polyorthoester, polycarbonate or polyamino
acid. The polymer or copolymer of a fatty acid ester can be
polylactic acid, polyglycolic acid, polycitric acid, polymalic
acid, or lactic/glycolic acid copolymer. Also disclosed as being
useful are poly(.alpha.-cyanoacrylic acid ester),
poly(.beta.-hydroxylactic acid), poly(tetramethylene oxalate),
poly(ethylene carbonate), poly-.gamma.-benzyl-L-glutamic acid, and
poly-L-alanine.
[0017] The antipsychotic (pref with mean particle diameter below 5
microns) is suspended in the biodegradable high polymer dissolved
in an oil solvent (boiling at 120.degree. C. or below), added to
water containing an emulsifier (such as an anionic or nonionic
surfactant, PVP, polyvinyl alcohol, CMC, lecithin or gelatine),
emulsified and dried.
[0018] The uses and advantages are said to be: administration of
the antipsychotic can be carried out by injection (e.g.,
subcutaneous or intramuscular) at extended intervals (e.g., every
one to eight weeks); compliance during antipsychotic maintenance
therapy is improved; the need for surgical implantation is avoided;
and administration is carried out with negligible discomfort.
[0019] 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.
[0020] In Ramstack et al., U.S. application Ser. No. 08/298,787,
the entirety of which is incorporated herein by reference, a
process was disclosed for preparing biodegradable, biocompatible
microparticles comprising a biodegradable, biocompatible polymeric
binder and a biologically active agent, wherein a blend of at least
two substantially non-toxic solvents, free of halogenated
hydrocarbons, was used to dissolve both the agent and the polymer.
The solvent blend containing the dissolved agent and polymer was
dispersed in an aqueous solution to form droplets. The resulting
emulsion was then added to an aqueous extraction medium preferably
containing at least one of the solvents of the blend, whereby the
rate of extraction of each solvent was controlled, whereupon the
biodegradable, biocompatible microparticles containing the
biologically active agent were formed. The preferred active agents
for encapsulation by this process were norethindrone, risperidone,
and testosterone and the preferred solvent blend was one comprising
benzyl alcohol and ethyl acetate.
[0021] Risperidone encapsulated in microparticles prepared using a
benzyl alcohol and ethyl acetate solvent system is also described
in Mesens et al., U.S. patent application Ser. No. 08/403,432, the
entirety of which is also incorporated herein by reference.
[0022] In the course of the continuing development of the
aforementioned microencapsulated risperidone product with the
ultimate goal of commercialization, it was discovered that the
maintenance of the product integrity upon long-term storage was a
problem, i.e., a degradation process was taking place. A need
therefore was found to exist for a means by which the degradation
rate could be reduced, thereby increasing the shelf-life of the
product and enhancing its commercial feasibility.
SUMMARY OF THE INVENTION
[0023] The present inventors discovered that, by reducing the level
of residual processing solvent, the rate of degradation of the
product could be significantly diminished. The present inventors
discovered that one degradation process resulted, at least in part,
from hydrolysis of the polymeric matrix, and that the rate of
hydrolysis was directly influenced by the level of residual
processing solvent, i.e., benzyl alcohol, in the product. By
reducing the level of residual solvent in the microparticles, the
rate of degradation was reduced, thereby increasing shelf-life.
[0024] The present invention relates to an improved 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, whereby the composition
exhibits increased shelf-life. The useful shelf-life can be
increased to about two or more years for microparticles made in
accordance with the method of the present invention. The invention
also relates to the novel composition, per se, which comprises at
least one active agent, at least one biocompatible, biodegradable
encapsulating binder, and less than about two percent by weight
residual solvent, the residual solvent being residual derived from
a solvent employed in the preparation of the microparticles.
[0025] More particularly, the present invention relates to a method
for preparing biodegradable, biocompatible microparticles
comprising:
[0026] A) preparing a first phase comprising:
[0027] (1) a biodegradable, biocompatible polymeric encapsulating
binder, and
[0028] (2) an active agent having limited water solubility
dissolved or dispersed in a first solvent;
[0029] B) preparing an aqueous second phase;
[0030] C) 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 is
continuous;
[0031] D) separating said discontinuous first phase from said
continuous second phase; and
[0032] E) washing said discontinuous first phase with
[0033] (1) water at a temperature in the range of from about
25.degree. C. to about 40.degree. C., or
[0034] (2) an aqueous solution comprising water and a second
solvent for residual first solvent in said first phase,
[0035] thereby reducing the level of residual first solvent to less
than about 2% by weight of said microparticles.
[0036] In a preferred aspect of the above-described process, a
quench step is additionally performed between steps C) and D).
[0037] The aqueous second phase can be an aqueous solution of a
hydrophilic colloid or a surfactant. The aqueous second phase can
be water.
[0038] In another aspect, the present invention relates to a method
for preparing biodegradable, biocompatible microparticles
comprising: preparing a first discontinuous phase (also referred to
herein as an "oil phase" or an "organic 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, biocompatible 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 co-solvents, each
having a solubility in water of from about 0.1 to about 25 weight
percent at 20.degree. 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 discontinuous first phase composition in a
continuous or "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, the quench
liquid containing the more water soluble co-solvent of the blend at
a level of from about 20% to about 70% of the saturation level of
the more water soluble co-solvent in the quench liquid at the
temperature being used; recovering microparticles from the quench
liquid; and washing the discontinuous first phase with water at an
elevated temperature (i.e., above room temperature) or with an
aqueous solution comprising water and a solvent for residual
solvent in the first phase, thereby reducing the level of residual
solvent in the microparticles. The level of residual solvent in the
microparticles is preferably reduced to about 2% by weight of the
microparticles.
[0039] In another aspect, the present invention relates to a method
for preparing biodegradable, biocompatible microparticles
comprising:
[0040] A) preparing a first phase comprising
[0041] 1) a biodegradable, biocompatible polymeric encapsulating
binder selected from the group consisting of poly(glycolic acid),
poly-d,l-lactic acid, poly-l-lactic acid, and copolymers of the
foregoing, and
[0042] 2) an active agent selected from the group consisting of
risperidone and 9-hydroxy risperidone, dissolved or dispersed in a
blend comprising ethyl acetate and benzyl alcohol, said blend being
free from halogenated hydrocarbons;
[0043] B) preparing a second phase comprising polyvinyl alcohol
dissolved in water;
[0044] C) combining said first phase and said second phase in a
static mixer to form an emulsion in which said first phase is
discontinuous and said second phase is continuous;
[0045] D) immersing said first and said second phases in a quench
liquid;
[0046] E) isolating said discontinuous first phase in the form of
microparticles; and
[0047] F) washing said discontinuous first phase with an aqueous
solution comprising water and ethanol, thereby reducing the level
of benzyl alcohol to less than about 2% by weight of said
microparticles.
[0048] In another aspect, the invention is directed to a method of
preparing biodegradable, bicompatible microparticles comprising:
preparing a first phase, said first phase comprising a biologically
active agent, a biodegradable, biocompatible polymer, and a first
solvent; 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; isolating said microparticles; and washing said
microparticles with water at an elevated temperature or with an
aqueous solution comprising water and a second solvent for residual
first solvent in said microparticles, thereby reducing the level of
residual first solvent to less than about 2% by weight of said
microparticles.
[0049] In further aspects of the invention, the first phase is
prepared by: dissolving the biologically active agent in a solution
of the polymer dissolved in a solvent free from halogenated
hydrocarbons; preparing a dispersion comprising the active agent in
the polymer solution; or preparing an emulsion comprising the
active agent in the polymer solution.
[0050] In another aspect, the present invention relates to a
pharmaceutical composition comprising biodegradable and
biocompatible microparticles in a pharmaceutically acceptable
carrier. The microparticles comprise a polymeric encapsulating
binder having dispersed or dissolved therein an active agent, and
less than about 2% by weight residual solvent, wherein the residual
solvent is residual derived from a solvent employed in the
preparation of the microparticles.
[0051] In another aspect, the present invention relates to a
pharmaceutical composition comprising biodegradable and
biocompatible microparticles, ranging in size from about 25 to
about 180 microns, in a pharmaceutically acceptable carrier. The
microparticles comprise a copolymer of poly(glycolic acid) and
poly(d,l-lactic acid) wherein the molar ratio of lactide to
glycolide is in the range of from about 85:15 to about 50:50 and
having dispersed or dissolved therein from about 35 to about 40% of
an active agent comprising risperidone or 9-hydroxy-risperidone,
and from about 0.5 to about 1.5% by weight of benzyl alcohol.
[0052] In yet another aspect, the invention provides a method for
preparing biodegradable, biocompatible microparticles that
comprises contacting microparticles comprising a biodegradable,
biocompatible polymer matrix containing an active agent and an
organic solvent with an aqueous washing system to thereby reduce
the level of residual organic solvent to less than about 2% by
weight of the microparticles. The aqueous washing system is: (1) at
a temperature of from about 25.degree. C. to about 40.degree. C.
for at least part of the contacting step; or (2) an aqueous
solution comprising water and a water-miscible solvent for the
organic solvent. The microparticles are recovered from the aqueous
washing system.
[0053] In the process of the invention, the initial content of
organic solvent in the microparticles will generally be above 3.5%,
more generally above 4.0% of the total weight of the
microparticles. Advantageously, the process will reduce this
content to less than 2%, preferably to less than 1.5% and most
preferably to less than 1%. The organic solvent preferably contains
a hydrophobic group containing at least 5 carbons, e.g., an aryl
group such as a naphthyl or more especially a phenyl group.
[0054] The organic solvent in the microparticles will generally be
present as a result of a particle formation process where the
microparticles have been produced from a solution of the matrix
forming polymer material in the organic solvent or in a solvent
mixture or blend containing the organic solvent.
[0055] The organic solvent will preferably be a non-halogenated
solvent. More preferably, the organic solvent will be an at least
partially water-miscible solvent, such as an alcohol (e.g., benzyl
alcohol), a linear or cyclic ether, a ketone or an ester (e.g.,
ethyl acetate).
[0056] Where used, a co-solvent in the solvent mixture or blend
likewise will preferably be a non-halogenated solvent and
particularly preferably will be an at least partially
water-miscible solvent such as an alcohol (e.g., a C.sub.1-4
alkanol such as ethanol), a linear or cyclic ether, a ketone or an
ester.
[0057] The contacting with the aqueous washing system may be
effected in one or more stages, e.g., a single contact or a series
of washes, optionally with differently constituted aqueous washing
systems. Preferably, the total contact time is for a period of ten
minutes to several hours, e.g., 1 to 48 hours.
[0058] The matrix forming polymer material should of course have
sufficiently limited solubility in the aqueous washing system used
that the particles do not dissolve completely in the washing system
during the contact period.
[0059] The process of the present invention may be carried out
using pre-formed microparticles or, more preferably, may
additionally comprise the production of the microparticles,
conveniently using a liquid phase containing as a solvent or
co-solvent the organic solvent referred to above, as well as the
matrix forming polymer and the active agent. Particle formation may
then be effected, for example, by spray drying or, more preferably,
by forming an emulsion using a second liquid phase, e.g., an
aqueous phase, with the first liquid phase being discontinuous and
the second being continuous as described above.
[0060] Viewed from a further aspect, the invention provides the use
of microparticles prepared by the process of the invention for the
manufacture of a medicament for use in a method of diagnosis or
therapy.
[0061] Viewed from a yet still further aspect, the invention
provides a method of treatment of the human or non-human (e.g.,
mammalian) animal body comprising the administration thereto of a
composition according to the invention.
ADVANTAGES OF THE INVENTION
[0062] Advantages of the method of the present invention are that
it provides, inter alia, a biodegradable, biocompatible system that
can be injected into a patient, the ability to mix microparticles
containing different drugs, microparticles free from halogenated
hydrocarbon residues, the ability to program release (multiphasic
release patterns) to give faster or slower rates of drug release as
needed, and improved shelf-life stability resulting from lowered
residual solvent in the finished product.
[0063] An advantage of the products prepared by the method of the
present invention is that durations of action ranging from 14 to
more than 200 days can be obtained, depending upon the type of
microparticle selected. In preferred embodiments, the
microparticles are designed to afford treatment to patients during
duration of action periods of 30 to 60 days and 60 to 100 days. A
90 day duration of action period is considered to be particularly
advantageous. The duration of action can be controlled by
manipulation of the polymer composition, polymer:drug ratio,
microparticle size, and concentration of residual solvent remaining
in the microparticle after treatment.
[0064] 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 present invention is biodegradable,
thereby permitting all of the entrapped active agent to be released
into the patient.
[0065] Still another important advantage of the microparticles
prepared by the process of the present invention is that residual
solvent(s) in the finished microparticle can be reduced by
approximately an order of magnitude whereby the useful shelf-life
of the product can be increased from about six months for product
made without the washing step of the present invention to about two
or more years for particles made with the washing step.
[0066] A further advantage of the process of the present invention
is that it may prove beneficial in controlling the release
characteristics of active agent in vivo or reducing an undesirable
or possibly harmful solvent.
BRIEF DESCRIPTION OF THE FIGURES
[0067] FIG. 1 depicts a graph showing the reduction in benzyl
alcohol levels in the finished product as a function of ethanol
concentration (5%; 15%; 20%; 25%) in an ethanol:water wash;
[0068] FIG. 2 depicts a graph showing the impact of microparticle
concentration on the level of residual benzyl alcohol (BA) in the
finished product;
[0069] FIG. 3 depicts a graph showing the impact of temperature of
the wash step on the level of residual benzyl alcohol (BA) in the
finished product; and
[0070] FIG. 4 depicts a graph showing the effect of the level of
residual solvent (benzyl alcohol) on the decay in molecular weight
of the polymeric matrix.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0071] To ensure clarity of the description that follows, the
following definitions are provided. By "microparticles" or
"microspheres" is meant solid particles that contain an active
agent dispersed or dissolved within a biodegradable, biocompatible
polymer that serves as the matrix of the particle. By "limited
water solubility" is meant having a solubility in water, in the
range of from about 0.1 to about 25 wt. % at 20.degree. C. By
"halogenated hydrocarbons" is meant halogenated organic solvents,
i.e., C.sub.1-C.sub.4 halogenated alkanes, e.g., methylene
chloride, chloroform, methyl chloride, carbon tetrachloride,
ethylene dichloride, ethylene chloride, 2,2,2-trichloroethane, and
the like. By "biodegradable" 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
biodegration should also be biocompatible with the body. By
"biocompatible" is meant not toxic to the human body, is
pharmaceutically acceptable, is not carcinogenic, and does not
significantly induce inflammation in body tissues. By "weight %" or
"% by weight" is meant parts by weight per total weight of
microparticle. For example, 10 wt. % agent would mean 10 parts
agent by weight and 90 parts polymer by weight.
[0072] In the process of the present invention, a solvent,
preferably free from halogenated hydrocarbons, is used to produce
biodegradable, biocompatible microparticles comprising at least one
biologically active agent. A particularly preferred solvent is a
solvent blend comprising at least two solvents. A first solvent
component of the solvent blend is a poor solvent for the active
agent, but is a good solvent for the biodegradable, biocompatible
polymer used herein. A second solvent component of the solvent
blend is a good solvent for the active agent. The active agent is
dissolved or dispersed in the solvent. Polymer matrix material is
added to the agent-containing medium 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.
[0073] The preferred solvent system is a blend of at least two
solvents. The solvents in the solvent blend are preferably:
[0074] (1) mutually miscible with one another,
[0075] (2) capable, when blended, of dissolving or dispersing the
active agent,
[0076] (3) capable, when blended, of dissolving polymeric matrix
material,
[0077] (4) chemically inert to the active agent,
[0078] (5) biocompatible,
[0079] (6) substantially immiscible with any quench liquid
employed, i.e., having a solubility from about 0.1 to 25%, and
[0080] (7) solvents other than halogenated hydrocarbons.
[0081] 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.degree. 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 of the encapsulating polymer and its
molecular weight.
[0082] The solvent system, although substantially immiscible with
the continuous phase process medium and any quenching liquid, which
usually are water or water-based, preferably has a limited
solubility therein. If the solvent system were infinitely soluble
in the process medium, microparticles would be unable to form
during the emulsion phase; if the solubility of the solvent system
in an extractive quenching medium were too low, however, large
quantities of quenching medium would be needed. Generally, solvent
solubilities of from about 0.1 to about 25% in the process medium
and any quench medium are acceptable for use herein. It will often
be advantageous for the quench medium, if employed, to contain from
about 70 to about 20 weight percent of the saturation point of the
first solvent, i.e., the solvent of higher solubility in the quench
medium, to control the rate of loss of the first solvent from the
microparticles into the quench medium.
[0083] Added considerations in choosing a component of the solvent
blend of the present invention include boiling point (i.e., the
ease with which the solvents can be evaporated, if desired, to form
finished product) and specific gravity (tendency of the
discontinuous or oil phase to float during emulsifying and
quenching). Finally, the solvent system should have low
toxicity.
[0084] Generally, the solvent blend composition of two components
will contain from about 25 to about 75 weight percent of the first
solvent, and, correspondingly, from about 75 to about 25 weight
percent of the second solvent.
[0085] Experiments using benzyl alcohol alone as the solvent did
result in control of microparticle size as determined by inspection
of the quench tank contents by optical microscopy. Upon drying,
however, generally poor quality was found to have resulted. Often,
recovery was difficult because of stickiness. Also, solvent
residuals tended to be elevated. Using a solvent system of ethyl
acetate and benzyl alcohol for the discontinuous or oil phase
improved the microparticle quality and release characteristics.
[0086] The solvent blend of the present invention is preferably a
blend of at least two of the following: an ester, an alcohol, and a
ketone. Preferred esters are of the structure R.sup.1COOR.sup.2
where R.sup.1 and R.sup.2 are independently selected from the group
consisting of alkyl moieties of from 1 to 4 carbon atoms, i.e.,
methyl, ethyl, propyl, butyl, and isomers thereof. The most
preferred ester for use as one component of the solvent blend
employed in the practice of the present invention is ethyl
acetate.
[0087] Preferred alcohols are of the structure R.sup.3CH.sub.2OH
where R.sup.3 is selected from the group consisting of hydrogen,
alkyl of from 1 to 3 carbon atoms, and aryl of from 6 to 10 carbon
atoms. It is more preferred that R.sup.3 be aryl. The most
preferred alcohol for use as one component of the solvent blend
employed in the practice of the present invention is benzyl
alcohol.
[0088] Preferred ketones are of the structure R.sup.4COR.sup.5
where R.sup.4 is selected from the group consisting of alkyl
moieties of from 1 to 4 carbon atoms, i.e., methyl, ethyl, propyl,
butyl, and isomers thereof and R.sup.5 is selected from the group
consisting of alkyl moieties of from 2 to 4 carbon atoms, i.e.,
ethyl, propyl, butyl, and isomers thereof The most preferred ketone
for use as one component of the solvent blend employed in the
practice of the present invention is methyl ethyl ketone.
[0089] The polymer matrix material of the microparticles prepared
by the process of the present invention is biocompatible and
biodegradable. The matrix material should be biodegradable in the
sense that it 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, as should any residual solvent that
may remain in the microparticles.
[0090] Preferred examples of polymer matrix materials include
poly(glycolic acid), poly(d,l-lactic acid), poly(l-lactic acid),
copolymers of the foregoing, and the like. Various commercially
available poly (lactide-co-glycolide) materials (PLGA) may be used
in the method of the present invention. For example, poly
(d,l-lactic-co-glycolic acid) is commercially available from
Medisorb Technologies International L.P. (Cincinnati, Ohio). A
suitable product commercially available from Medisorb is a 50:50
poly (d,l lactic co-glycolic acid) known as MEDISORB.RTM. 50:50 DL.
This product has a mole percent composition of 50% lactide and 50%
glycolide. Other suitable commercially available products are
MEDISORB.RTM. 65:35 DL, 75:25 DL, 85:15 DL and poly(d,l-lactic
acid) (d,l-PLA). Poly(lactide-co-glycolides) are also commercially
available from Boehringer Ingelheim (Germany) under its Resomer
mark, e.g., PLGA 50:50 (Resomer RG 502), PLGA 75:25 (Resomer RG
752) and d,l-PLA (Resomer RG 206), and from Birmingham Polymers
(Birmingham, Alabama). These copolymers are available in a wide
range of molecular weights and ratios of lactic acid to glycolic
acid.
[0091] The most preferred polymer for use in the practice of this
invention is the copolymer, poly(d,l-lactide-co-glycolide). It is
preferred that the molar ratio of lactide to glycolide in such a
copolymer be in the range of from about 85:15 to about 50:50.
[0092] It will be understood that the problem addressed by the
process of the present invention is the undesirably short
shelf-life engendered by the action of an active agent on the
matrix polymer where the solvent, or at least one of the solvents
of the solvent blend, used in making the microparticles remains in
sufficient concentration in the finished product to exacerbate
degrading interaction between the active agent and the polymer.
This problem can be seen, for example, with an active agent having
a basic moiety, such as risperidone, and a matrix polymer that has
a group or linkage susceptible to base-catalyzed hydrolysis. Those
skilled in the art will readily comprehend, however, that the
concept of the present invention is broader than the shelf-life
problem described, and is, rather, directed to the more general
solution of washing products having particular tenacious solvent
residuals with a wash liquid comprising water and a water miscible
solvent for the tenacious solvent(s) in the product.
[0093] The molecular weight of the polymeric matrix material is of
some importance. The molecular weight should be high enough to
permit the formation of satisfactory polymer coatings, i.e., the
polymer should be a good film former. Usually, a satisfactory
molecular weight is in the range of 5,000 to 500,000 daltons,
preferably about 150,000 daltons. However, since the properties of
the film are also partially dependent on the particular polymeric
matrix material being used, it is very difficult to specify an
appropriate molecular weight range for all polymers. The molecular
weight of a polymer is also important from the point of view of its
influence upon the biodegradation rate of the polymer. For a
diffusional mechanism of drug release, the polymer should remain
intact until all of the drug is released from the microparticles
and then degrade. The drug can also be released from the
microparticles as the polymeric excipient 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.
[0094] Those skilled in the art will comprehend that removal of
residual solvent by the wash step of the present invention may have
an effect upon the drug release rate, which may be either
detrimental or beneficial, depending upon the circumstances. For
example, where the residual solvent is acting as a plasticizer for
the matrix polymer, the glass transition temperature may be seen to
decrease, thereby possibly accelerating the release rate of the
active agent. If, in a given situation, a faster release rate is
desirable, this result will be beneficial. If, however, the rate
becomes fast enough to negatively affect the desired action of the
active agent with regard to the patient, it will be incumbent upon
the formulator to employ means for alleviating the accelerated
release rate. Such modifications of the process, when required, are
within the capability of those of ordinary skill in the relevant
arts and can be realized without undue experimentation.
[0095] The formulation prepared by the process of the present
invention contains an active agent dispersed in the microparticle
polymetric matrix material. The amount of such agent incorporated
in the microparticles usually ranges from about 1 wt. % to about 90
wt. %, preferably 30 to 50 wt. %, more preferably 35 to 40
wt.%.
[0096] In carrying out the process of the present invention, the
encapsulating polymer should be essentially 100% dissolved in the
solvent or solvent blend at the time the solution is emulsified.
The active agent can be dispersed or dissolved in the solvent or
solvent blend at the time it is added to the continuous phase
process medium. The content of normally solid material (active
agent plus encapsulating polymer) in the solvent blend at the time
it is first emulsified should be at least 5 weight percent and
preferably at least 20 weight percent. Minimizing solvent in the
discontinuous or oil phase provides a better quality microparticle
and requires less extraction medium.
[0097] Preferred active agents that can be encapsulated by the
process of the present invention are those that comprise at least
one basic moiety. Particularly preferred active agents that can be
encapsulated by the process of the present invention are
1,2-benzazoles; more particularly, 3-piperidinyl-substituted
1,2-benzisoxazoles and 1,2benzisothiazoles. The most preferred
active agents of this kind for treatment by the process of the
present invention are
3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-pipe-
ridinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H--pyrido[1,2-a]pyrimidin-4-on-
e ("risperidone") and
3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidin-
yl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H--pyrido[1,2-a]pyrimidin-
-4-one ("9-hydroxyrisperidone") and the pharmaceutically acceptable
salts thereof. Risperidone (which term, as used herein, is intended
to include its pharmaceutically acceptable salts) is most
preferred.
[0098] Other biologically active agents that can be incorporated
using the process of the present invention include gastrointestinal
therapeutic agents such as aluminum hydroxide, calcium carbonate,
magnesium carbonate, sodium carbonate and the like; non-steroidal
antifertility agents; parasympathomimetic agents; psychotherapeutic
agents; major tranquilizers such as chlorpromazine HCl, clozapine,
mesoridazine, metiapine, reserpine, thioridazine and the like;
minor tranquilizers such as chlordiazepoxide, diazepam,
meprobamate, temazepam and the like; rhinological decongestants;
sedative-hypnotics such as codeine, phenobarbital, sodium
pentobarbital, sodium secobarbital and the like; steroids such as
testosterone and testosterone propionate; sulfonamides;
sympathomimetic agents; vaccines; vitamins and nutrients such as
the essential amino acids; essential fats and the like;
antimalarials such as 4-aminoquinolines, 8-aminoquinolines,
pyrimethamine and the like, anti-migraine agents such as mazindol,
phentermine and the like; anti-Parkinson agents such as L-dopa;
anti-spasmodics such as atropine, methscopolamine bromide and the
like; antispasmodics and anticholinergic agents such as bile
therapy, digestants, enzymes and the like; antitussives such as
dextromethorphan, noscapine and the like; bronchodilators;
cardiovascular agents such as anti-hypertensive compounds,
Rauwolfia alkaloids, coronary vasodilators, nitroglycerin, organic
nitrates, pentaethritotetranitrate and the like; electrolyte
replacements such as potassium chloride; ergotalkaloids such as
ergotamine with and without caffeine, hydrogenated ergot alkaloids,
dihydroergocristine methanesulfate, dihydroergocornine
methanesulfonate, dihydroergokroyptine methanesulfate and
combinations thereof; alkaloids such as atropine sulfate,
Belladonna, hyoscine hydrobromide and the like; analgetics;
narcotics such as codeine, dihydrocodienone, meperidine, morphine
and the like; non-narcotics such as salicylates, aspirin,
acetaminophen, d-propoxyphene and the like; antibiotics such as the
cephalosporins, chloranphenical, gentamicin, Kanamycin A, Kanamycin
B, the penicillins, ampicillin, streptomycin A, antimycin A,
chloropamtheniol, metromidazole, oxytetracycline penicillin G, the
tetracyclines, and the like; anti-cancer agents; anti-convulsants
such as mephenytoin, phenobarbital, trimethadione; anti-emetics
such as thiethylperazine; antihistamines such as chlorophinazine,
dimenhydrinate, diphenhydramine, perphenazine, tripelennamine and
the like; anti-inflammatory agents such as hormonal agents,
hydrocortisone, prednisolone, prednisone, non-hormonal agents,
allopurinol, aspirin, indomethacin, phenylbutazone and the like;
prostaglandins; cytotoxic drugs such as thiotepa, chlorambucil,
cyclophosphamide, melphalan, nitrogen mustard, methotrexate and the
like; antigens of such microorganisms as Neisseria gonorrhea,
Mycobacterium tuberculosis, Herpes virus (humonis, types 1 and 2),
Candida albicans, Candida tropicalis, Trichomonas vaginalis,
Haemophilus vaginalis, Group B Streptococcus ecoli, Microplasma
hominis, Hemophilus ducreyi, Granuloma inguinale, Lymphopathia
venereum, Treponema pallidum, Brucella abortus, Brucella
melitensis, Brucella suis, Brucella canis, Campylobacter fetus,
Campylobacter fetus intestinalis, Leptospira pomona, Listeria
monocytogenes, Brucella ovis, Equine herpes virus 1, Equine
arteritis virus, IBR-IBP virus, BVD-MB virus, Chlamydia psittaci,
Trichomonas foetus, Toxoplasma gondii, Escherichia coli,
Actinobacillus equuli, Salmonella abortus ovis, Salmonella abortus
equi, Pseudomonas aeruginosa, Corynebacterium equi, Corynebacterium
pyogenes, Actinobaccilus seminis, Mycoplasma bovigenitalium,
Aspergillus fumigatus, Absidia ramosa, Trypanosoma equiperdum,
Babesia caballi, Clostridium tetani, and the like; antibodies that
counteract the above microorganisms; and enzymes such as
ribonuclease, neuramidinase, trypsin, glycogen phosphorylase, sperm
lactic dehydrogenase, sperm hyaluronidase, adenosinetriphosphatase,
alkaline phosphatase, alkaline phosphatase esterase, amino
peptidase, trypsin, chymotrypsin, amylase, muramidase, acrosomal
proteinase, diesterase, glutamic acid dehydrogenase, succinic acid
dehydrogenase, beta-glycophosphatase, lipase, ATP-ase alpha-peptate
gamma-glutamylotranspeptidase, sterol-3-beta-ol-dehydrogenase, and
DPN-di-aprorase.
[0099] Other suitable active agents include estrogens such as
diethyl stilbestrol, 17-beta-estradiol, estrone, ethinyl estradiol,
mestranol, and the like; progestins such as norethindrone,
norgestryl, ethynodiol diacetate, lynestrenol, medroxyprogesterone
acetate, dimesthisterone, megestrol acetate, chlormadinone acetate,
norgestimate, norethisterone, ethisterone, melengestrol,
norethynodrel and the like; and spermicidal compounds such as
nonylphenoxypolyoxyethylene glycol, benzethonium chloride,
chlorindanol and the like.
[0100] Still other macromolecular bioactive agents that may be
chosen for incorporation include, but are not limited to, blood
clotting factors, hemopoietic factors, cytokines, interleukins,
colony stimulating factors, growth factors, and analogs and
fragments thereof.
[0101] The microparticles can be mixed by size or by type so as to
provide for the delivery of active agent to the patient in a
multiphasic manner and/or in a manner that provides different
active agents to the patient at different times, or a mixture of
active agents at the same time. For example, secondary antibiotics,
vaccines, or any desired active agent, either in microparticle form
or in conventional, unencapsulated form can be blended with a
primary active agent and provided to the patient.
[0102] The mixture of ingredients in the discontinuous or oil phase
solvent system is emulsified in a continuous-phase processing
medium; the continuous-phase medium being such that a dispersion of
microparticles containing the indicated ingredients is formed in
the continuous-phase medium.
[0103] Although not absolutely necessary, it is preferred to
saturate the continuous phase process medium with at least one of
the solvents forming the discontinuous or oil phase solvent system.
This provides a stable emulsion, preventing transport of solvent
out of the microparticles prior to quenching. Similarly, a vacuum
may be applied as in U.S. Pat. No. 4,389,330. Where ethyl acetate
and benzyl alcohol are the components of the solvent system, the
aqueous or continuous phase of the emulsion preferably contains 1
to 8 weight percent ethyl acetate and 1 to 4 weight percent benzyl
alcohol.
[0104] Usually, a surfactant or a hydrophilic colloid is added to
the continuous-phase processing medium to prevent the solvent
microdroplets from agglomerating and to control the size of the
solvent microdroplets in the emulsion. Examples of compounds that
can be used as surfactants or hydrophilic colloids include, but are
not limited to, poly(vinyl alcohol), carboxymethyl cellulose,
gelatin, poly(vinyl pyrrolidone), Tween 80, Tween 20, and the like.
The concentration of surfactant or hydrophilic colloid in the
process medium should be sufficient to stabilize the emulsion and
will affect the final size of the microparticles. Generally the
concentration of the surfactant or hydrophilic colloid in the
process medium will be from about 0.1% to about 10% by weight based
on the process medium, depending upon the surfactant or hydrophilic
colloid, the discontinuous or oil phase solvent system, and the
processing medium used. A preferred dispersing medium combination
is a 0.1 to 10 wt. %, more preferably 0.5 to 2 wt. %, solution of
poly(vinyl alcohol) in water.
[0105] The emulsion can be formed by mechanical agitation of the
mixed phases or by adding small drops of the discontinuous phase
that contains active agent and wall forming material to the
continuous phase processing medium. The temperature during the
formation of the emulsion is not especially critical, but can
influence the size and quality of the microparticles and the
solubility of the active agent in the continuous phase. Of course,
it is desirable to have as little of the active agent in the
continuous phase as possible. Moreover, depending upon the solvent
blend and continuous-phase processing medium employed, the
temperature must not be too low or the solvent and processing
medium may solidify or become too viscous for practical purposes.
On the other hand, it must not be so high that the processing
medium will evaporate or that the liquid processing medium will not
be maintained. Moreover, the temperature of the emulsion cannot be
so high that the stability of the particular active agent being
incorporated in the microparticles is adversely affected.
Accordingly, the dispersion process can be conducted at any
temperature that maintains stable operating conditions, preferably
from about 20.degree. C. to about 60.degree. C., depending upon the
active agent and excipient selected.
[0106] As stated above, in order to create microparticles
containing an active agent, an organic or oil (discontinuous) phase
and an aqueous phase are combined. The organic and aqueous phases
are largely or substantially immiscible, with the aqueous phase
constituting the continuous phase of the emulsion. The organic
phase includes the active agent as well as the wall forming
polymer, i.e., the polymeric matrix material. The organic phase is
prepared by dissolving or dispersing the active agent(s) in the
organic solvent system of the present invention. The organic phase
and the aqueous phase are preferably combined under the influence
of mixing means.
[0107] A preferred type of mixing means is a static mixer and a
preferred method of encapsulating the active agent to form the
controlled release microparticles of the present invention involves
the use of such a static mixer. Preferably the combined organic and
aqueous phases are pumped through a static mixer to form an
emulsion and into a large volume of quench liquid, to obtain
microparticles containing the active agent encapsulated in the
polymeric matrix material. An especially preferred method of mixing
with a static mixer in the process of the present invention is
disclosed by Ramstack et al. in U.S. application Ser. No.
08/338,805, the entirety of which is incorporated herein by
reference.
[0108] One advantage of preparing microparticles using a static
mixer 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. A further advantage
of this method is that the same equipment can be used to form
microparticles containing active agents of a well defined size
distribution for varying batch sizes. In addition to improving
process technology, static mixers are low maintenance, their small
size requires less space than dynamic mixers, and they have low
energy demands and comparatively low investment costs.
[0109] In practice, the organic phase and the aqueous phase are
mixed in a static mixer to form an emulsion. The emulsion formed
comprises microparticles containing active agent encapsulated in
the polymeric matrix material. Preferably, the microparticles are
then stirred in a tank containing a quench solution in order to
remove most of the organic solvent from the microparticles,
resulting in the formation of hardened microparticles.
[0110] Following the movement of the microparticles from the static
mixer and entrance into the quench tank, the continuous-phase
processing medium is diluted and much of the solvent in the
microparticles is removed by extraction. In this extractive quench
step, the microparticles can be suspended in, the same
continuous-phase processing medium used during emulsification, with
or without hydrophilic colloid or surfactant, or in another liquid.
The extraction medium removes a significant portion of the solvent
from the microparticles, but does not dissolve them. During the
extraction, the extraction medium containing dissolved solvent can,
optionally, be removed and replaced with fresh extraction
medium.
[0111] After the quench step has been completed, the microparticles
can be isolated as stated above, and then may, if desired, be dried
by exposure to air or by other conventional drying techniques, such
as, vacuum drying, drying over a desiccant, or the like. This
process is very efficient in encapsulating an active agent since
core loadings of up to about 80 wt. %, preferably up to about 50
wt. %, can be obtained.
[0112] When a solvent blend is used to form the organic or oil
phase droplets in the emulsion, one of the solvents in the solvent
blend will be extracted in the quench step more quickly than the
other solvent, e.g., the first solvent, ethyl acetate, in the case
of the preferred ethyl acetate/benzyl alcohol blend. Thus, high
residuals of the second solvent (here, benzyl alcohol) are left
behind. Owing to the high boiling point of benzyl alcohol, it is
not easily removed by exposure of the microparticles to air or
other conventional evaporative means. To improve the efficiency of
this procedure, some of the more rapidly extracted solvent can be
added to the quench extraction medium prior to addition of the
emulsion. The concentration of the more-rapidly-extracted solvent
in the quench extraction medium generally is from about 20 to about
70% of the saturation point of the solvent in the medium at the
temperature to be used for the extraction. Thus, when the emulsion
is added to the quench liquid, extraction of the more rapidly
extracted solvent is retarded and more of the second, more slowly
extracted, solvent is removed.
[0113] The exact amount of this more-rapidly-extracted solvent
"spike" added to the quench liquid is of importance to final
microparticle quality. Too much solvent (i.e., near the saturation
point) results in porous microparticles with active agent visible
on the surface, causing what may be an undesirably high rate of
release. Too little solvent in the quench medium results in high
residual level of the more-slowly-extracted solvent and poor
microparticle quality. The temperature of the quench medium is also
important as it affects solvent solubility and rate of
extraction.
[0114] Both temperature and amount of solvent spike can be adjusted
to contribute beneficially to the final desired product
characteristics, i.e., highly porous, quick releasing
microparticles, or slow releasing microparticles having a low
porosity.
[0115] The quench liquid can be plain water, a water solution, or
other suitable liquid, the volume, amount, and type of which
depends on the solvents used in the emulsion phase. The quench
liquid is preferably water. Generally, the quench liquid volume is
on the order of 10 times the saturated volume (i.e., 10 times the
quench volume needed to absorb completely the volume of solvent in
the emulsion). Depending on the solvent system, however, quench
volume can vary from about 2 to about 20 times the saturated
volume. Additionally, it is convenient to describe the quench
volume requirement relative to batch size (microparticle product).
This ratio is an indication of efficiency of the extraction step
and, in some cases, dictates the batch size for a given set of
equipment. The larger the ratio, the more volume is required per
product weight. On the other hand, with a smaller ratio, more
product can be obtained from the same amount of quench volume. This
ratio can vary from about 0.1 to about 10 liters of quench volume
per gram of microparticles produced. Processes with a ratio of less
than about 1 liter per gram are preferred.
[0116] When using the preferred solvent combination of benzyl
alcohol and ethyl acetate, the ethyl acetate content of the quench
liquid appears to affect the residual solvent level in the product
microparticles. At low ethyl acetate contents in the quench liquid,
the benzyl alcohol residuals in the microparticles are high while
ethyl acetate may be almost non-detectable. At high ethyl acetate
contents in the quench liquid, more ethyl acetate may be retained
by the microparticles than benzyl alcohol. At a quench volume of
about 1 liter per gram of active agent and polymeric encapsulating
material being quenched, about 2-4 weight percent ethyl acetate in
the quench liquid is optimal at 0-10.degree. C.
[0117] After the quenching step, the microparticles are isolated
from the aqueous quench solution by any convenient means of
separation--the fluid can be decanted from the microparticles or
the microparticle suspension can be filtered, for example, a sieve
column can be used. Various other combinations of separation
techniques can be used, if desired. Filtration is preferred.
[0118] The filtered microparticles are then subjected to the
washing step of the present invention in order to reduce still
further the level of residual solvent(s) therein, preferably to a
level in the range of from about 0.2 to about 2.0%. In practice, it
has been found that, in the preferred ethyl acetate/benzyl alcohol
dual solvent case, residual benzyl alcohol levels are still
generally in the 4-8% range without the washing step of the present
invention. This level of residual solvent in the microparticles
appears to be sufficient to accelerate the degradation process,
thereby reducing shelf-life. Degradation of the microparticles can
occur, for example, by undesired hydrolysis of the hydrolyzable
linkages of a matrix polymer by a basic active agent. Thus, the
washing step(s) of the present invention are employed to reduce the
residual benzyl alcohol or other solvent content in the
microparticles to retard the degradation process.
[0119] As stated above, the wash solution comprises either water
alone or, preferably, water and a solvent miscible therewith that
is also a good solvent for the residual solvent in the
microparticles. Where, as in the preferred process of the present
invention, the residual solvent is benzyl alcohol, C.sub.1-C.sub.4
aliphatic alcohols are preferred for use in the wash solution.
These alcohols are methanol, ethanol, propanol, butanol, and
isomers of the foregoing. The most preferred alcohol is
ethanol.
[0120] The concentration of the alcohol in the wash solution can
vary depending upon the particular circumstances. Generally, the
alcohol will comprise less than 50% by weight with a lower limit of
about 5%. Thus, a preferred range for the alcohol concentration
with normally be from about 5% to about 50% by weight. More
preferably, the concentration will lie in the range of from about
15% to about 30%.
[0121] The temperature of the wash solution is also important to
the efficiency of the washing step. Generally, increasing the
temperature will decrease the time needed for the wash to lower the
remaining residual content to the desired level. On the other hand,
too high a temperature can be detrimental in that the softening
temperature of the matrix polymer of the microparticles may be
approached or exceeded, thereby causing clumping or stickiness.
Conversely, too low a temperature may cause the matrix material to
become too hard, thereby retarding the rate at which the residuals
can be extracted, whereby the process may become prohibitively
expensive. It has been found that a temperature range of from about
5.degree. C. to about 40.degree. C. is convenient and effective.
Preferably, the temperature employed will bracket room temperature,
i.e., from about 10.degree. C. to about 30.degree. C. Where water
alone is used as the wash solvent, it will be employed at an
elevated temperature, i.e., above room temperature, preferably in a
range of from about 25.degree. C. to about 40.degree. C., most
preferably, about 37.degree. C.
[0122] Normally, it will be desirable to employ more than one wash
step, typically two or three. After each such step, the
microparticles will be separated from the wash solution by
well-known separation means, e.g., filtration, decantation,
centrifugation, and the like. Filtration is preferred.
[0123] After each separation step, the microparticles can, if
desired, be fully or partially dried employing conventional drying
means at temperatures substantially similar to those of the
previous wash solution. The use of dry compressed air at
temperatures ranging from about 10.degree. C. to about 30.degree.
C. has been found especially useful and convenient and is
preferred.
[0124] The microparticle product is usually made up of particles of
a spherical shape, although sometimes the microparticles may be
irregularly shaped. The microparticles can vary in size, ranging
from submicron to millimeter diameters. Preferably, microparticles
of 1-500 microns, more preferably, 25-180 microns, are prepared,
whereby administration of the microparticles to a patient can be
carried out with a standard gauge needle.
[0125] Preferably, the drug-loaded microparticles are dispensed to
patients in a single administration, releasing the drug in a
constant or pulsed manner into the patient and eliminating the need
for repetitive injections.
[0126] The active agent bearing microparticles are obtained and
stored as a dry material. Prior to administration to a patient, the
dry microparticles can be suspended in an acceptable pharmaceutical
liquid vehicle, such as, a 2.5 wt. % solution of carboxymethyl
cellulose, whereupon the suspension is injected into the body.
[0127] The microparticles can be mixed by size or by type so as to
provide for the delivery of active agent to the patient in a
multiphasic manner and/or in a manner that provides different
active agents to the patient at different times, or a mixture of
active agents at the same time. For example, secondary antibiotics,
vaccines, or any desired active agent, either in microparticle form
or in conventional, unencapsulated form can be blended with a
primary active agent and provided to the patient.
[0128] Those skilled in the art will understand that any of the
numerous active agents that can be incorporated into microparticles
can be prepared by the process of the present invention. Preferred
active agents for use with the process of the present invention are
those that contain at least one basic moiety, such as a tertiary
amine group. Particularly, preferred active agents for treatment by
the process of the present invention are risperidone and
9-hydroxyrisperidone and the pharmaceutically acceptable salts
thereof. For those materials that have no groups detrimental to the
integrity of the matrix polymer, the additional washing step(s) of
the present invention may prove beneficial in ways, such as,
controlling the release characteristics of active agent in vivo or
reducing an undesirable or possibly harmful solvent.
[0129] The following examples further describe the materials and
methods used in carrying out the invention. The examples are not
intended to limit the invention in any manner.
EXAMPLE 1
[0130] In a typical 125 gram batch, 75 g of 75:25 Medisorb.RTM.
lactide:glycolide copolymer and 50 g of risperidone are dissolved
in 275 g of benzyl alcohol and 900.25 g of ethyl acetate as the
organic phase. The aqueous phase comprises 90.0 g of polyvinyl
alcohol, 8910 g of water, 646.4 g of ethyl acetate, and 298.3 g of
benzyl alcohol. The organic and aqueous phases are pumped through a
static mixer to form an emulsion. The resulting emulsion is passed
into a quench liquid comprising 17 kg of water, 4487.8 g of ethyl
acetate, 371.0 g of sodium carbonate, and 294.0 g of sodium
bicarbonate. After 20 hours at approximately 10.degree. C., the
resulting microspheres are then filtered and washed with a first
wash of 11.25 kg of ethanol and 33.75 kg of water for 2 hours at
10.degree. C. The microspheres are then filtered and washed with a
solution of 11.25 kg of ethanol and 33.75 kg of water for 6 hours
at 25.degree. C. A third wash of 756 g of citric acid, 482 g of
sodium phosphate, and 45.0 kg of water is then applied at
25.degree. C. for one hour to the filtered product. The product is
then rinsed with water, filtered, and dried. Three batches produced
according to this procedure provide risperidone contents of 37.4%,
37.0%, and 36.6% by weight. Benzyl alcohol levels were 1.36%,
1.26%, and 1.38% by weight. Ethyl acetate levels were 0.09%, 0.08%,
and 0.09% by weight.
EXAMPLE 2
Effect of the Wash Process on Microparticle Characteristics
[0131] A sample of risperidone-loaded microspheres was subjected to
a series of wash experiments to determine the impact on finished
product characteristics and identify favorable wash conditions. The
sample comprised risperidone encapsulated in a 75:25 Medisorb.RTM.
lactide:glycolide copolymer. The drug content was 36.8% by weight,
and the benzyl alcohol level was about 5.2% by weight prior to the
washing experiments. The microspheres were transferred into the
wash media, samples were withdrawn at selected time periods and
vacuum dried.
[0132] FIG. 1 shows the reduction in benzyl alcohol levels in the
finished product as a function of ethanol concentrations (5%; 15%;
20%; and 25%) in the ethanol:water wash. Higher ethanol levels
afforded lower residual benzyl alcohol in the finished product.
[0133] FIG. 2 shows that in the range of 0.1 to 1.0 liters of
solution per gram of microspheres, the concentration of
microspheres in the wash step does not influence the level of
residual benzyl alcohol (BA) in the finished product.
[0134] FIG. 3 shows the impact of temperature of the wash step on
the level of residual benzyl alcohol in the finished product.
[0135] Table 1 shows an increase in glass-transition temperature
(T.sub.g) of the finished microspheres as the wash time increases,
and as the concentration of ethanol increases and the corresponding
concentration of benzyl alcohol decreases.
1TABLE 1 Effect of Ethanol Wash Time and Concentration on Glass
Transition Temperature, T.sub.g Wash Time 5% 15% 20% 25% (Hours)
Ethanol Ethanol Ethanol Ethanol 0.75 24.2 .degree. C. 26.5 .degree.
C. 30.1 .degree. C. 30.8 .degree. C. 3 26.5 .degree. C. 26.5
.degree. C. 32.5 .degree. C. 35.1 .degree. C. 24 30.9 .degree. C.
28.7 .degree. C. 37.3 .degree. C. 40.1 .degree. C.
[0136] Risperidone-loaded microspheres with various levels of
benzyl alcohol were placed in stability studies at room
temperature. FIG. 4 demonstrates that the degradation process as
measured by the rate of hydrolysis of the biodegradable,
biocompatible polymer is strongly influenced by the level of
residual solvent in the finished product. The molecular weight
decay constant was plotted versus residual benzyl alcohol level for
ten different microsphere samples.
[0137] While various embodiments of the present invention have been
described above, it should be understood that they have been
presented by way of example only, and not limitation. Thus the
breadth and scope of the present invention should not be limited by
any of the above described exemplary embodiments, but should be
defined only in accordance with the following claims and their
equivalents.
* * * * *