U.S. patent application number 10/352241 was filed with the patent office on 2003-07-31 for method for preparing microparticles having a selected polymer molecular weight.
This patent application is currently assigned to Alkermes Controlled Therapeutics Inc. II. Invention is credited to Hotz, Joyce M., Lyons, Shawn L., Ramstack, J. Michael, Rickey, Michael E., Wright, Steven G..
Application Number | 20030143279 10/352241 |
Document ID | / |
Family ID | 24298824 |
Filed Date | 2003-07-31 |
United States Patent
Application |
20030143279 |
Kind Code |
A1 |
Wright, Steven G. ; et
al. |
July 31, 2003 |
Method for preparing microparticles having a selected polymer
molecular weight
Abstract
A method for preparing microparticles having a selected polymer
molecular weight. The hold time and temperature of a solution
containing a nucleophilic compound and a polymer having a starting
molecular weight are controlled in order to control the molecular
weight of the polymer in the finished microparticle product. In
this manner, a selected polymer molecular weight in the finished
microparticle product can be achieved from a variety of starting
material molecular weights.
Inventors: |
Wright, Steven G.; (Madeira,
OH) ; Rickey, Michael E.; (Loveland, OH) ;
Ramstack, J. Michael; (Lebanon, OH) ; Lyons, Shawn
L.; (Cincinnati, OH) ; Hotz, Joyce M.;
(Cincinnati, OH) |
Correspondence
Address: |
COVINGTON & BURLING
ATTN: PATENT DOCKETING
1201 PENNSYLVANIA AVENUE, N.W.
WASHINGTON
DC
20004-2401
US
|
Assignee: |
Alkermes Controlled Therapeutics
Inc. II
88 Sidney Street
Cambridge
MA
02139-4136
|
Family ID: |
24298824 |
Appl. No.: |
10/352241 |
Filed: |
January 28, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10352241 |
Jan 28, 2003 |
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10073864 |
Feb 14, 2002 |
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6534092 |
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10073864 |
Feb 14, 2002 |
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09870751 |
Jun 1, 2001 |
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6379704 |
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09870751 |
Jun 1, 2001 |
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09575075 |
May 19, 2000 |
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6264987 |
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Current U.S.
Class: |
424/490 ;
264/4.1 |
Current CPC
Class: |
A61K 9/1647 20130101;
B01J 13/02 20130101; A61K 31/519 20130101; A61K 9/1694
20130101 |
Class at
Publication: |
424/490 ;
264/4.1 |
International
Class: |
A61K 009/14; A61K
009/16; A61K 009/50 |
Claims
What Is claimed is:
1. A method of preparing microparticles having a selected
microparticle polymer molecular weight, comprising: (a) combining a
first phase comprising a nucleophilic compound, a polymer having a
starting molecular weight, and a solvent for the polymer, with a
second phase to form an emulsion; (b) extracting solvent from the
emulsion, thereby forming microparticles; and (c) maintaining the
first phase at a hold temperature for a hold period prior to step
(a), the hold period of sufficient duration to allow the starting
molecular weight of the polymer to reduce so that the selected
microparticle polymer molecular weight is achieved.
2. The method of claim 1, further comprising: (d) increasing the
hold temperature, thereby increasing molecular weight decay of the
polymer to reduce a duration of the hold period.
3. The method of claim 1, further comprising: (d) decreasing the
hold temperature, thereby decreasing molecular weight decay of the
polymer to increase a duration of the hold period.
4. The method of claim 1, wherein the starting molecular weight is
in the range of from about 50 kD to about 250 kD.
5. The method of claim 1, wherein the hold period is in the range
of from about 0.05 hour to about 6 hours.
6. The method of claim 1, wherein the hold temperature is in the
range of from about 15.degree. C. to about 35.degree. C.
7. The method of claim 1, wherein step (b) comprises combining the
emulsion and an extraction medium.
8. The method of claim 1, wherein the nucleophilic compound is
selected from the group consisting of risperidone, 9
-hydroxyrisperidone, and pharmaceutically acceptable salts
thereof.
9. The method of claim 8, wherein the solvent comprises benzyl
alcohol and ethyl acetate.
10. The method of claim 1, wherein the 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.
11. The method of claim 10, wherein the polymer is
poly(d,l-lactide-co-gly- colide) having a molar ratio of lactide to
glycolide in the range of from about 100:0 to about 50:50.
12. The method of claim 1, further comprising: (d) mixing the first
phase during the hold period.
13. The method of claim 1, wherein the selected microparticle
polymer molecular weight is in the range of from about 10 kD to
about 185.0 kD.
14. The method of claim 4, wherein the selected microparticle
polymer molecular weight is in the range of from about 10 kD to
about 185.0 kD.
15. The method of claim 1, wherein the starting molecular weight
reduces by an amount in the range of from about 10% to about 50% to
reach the selected microparticle polymer molecular weight.
16. The method of claim 4, wherein the starting molecular weight
reduces by an amount in the range of from about 10% to about 50% to
reach the selected microparticle polymer molecular weight.
17. The method of claim 13, wherein the starting molecular weight
reduces by an amount in the range of from about 10% to about 50% to
reach the selected microparticle polymer molecular weight.
18. The method of claim 1, further comprising: (d) adding an
inactive agent to the first phase.
19. The method of claim 1, wherein the nucleophilic compound is an
active agent.
20. The method of claim 1, wherein the nucleophilic compound is an
inactive agent.
21. The method of claim 1, wherein the nucleophilic compound is
basic.
22. The method of claim 1, wherein the nucleophilic compound is
naltrexone.
23. The method of claim 1, wherein the nucleophilic compound is
oxybutynin.
24. Microparticles having a selected microparticle polymer
molecular weight prepared by the method of claim 1.
25. Microparticles having a selected microparticle polymer
molecular weight prepared by the method of claim 8.
26. Microparticles having a selected microparticle polymer
molecular weight prepared by the method of claim 10.
27. Microparticles having a selected microparticle polymer
molecular weight prepared by the method of claim 22.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to preparation of
microparticles. More particularly, the present invention relates to
a method and an apparatus for preparing microparticles having a
selected polymer molecular weight.
[0003] 2. Related Art
[0004] A variety of methods is known by which compounds can be
encapsulated in the form of microparticles. It is particularly
advantageous to encapsulate a biologically active or
pharmaceutically active agent within a biocompatible, biodegradable
wall forming material (e.g., a polymer) to provide sustained or
delayed release of drugs or other active agents. In these methods,
the material to be encapsulated (drugs or other active agents) is
generally dissolved, dispersed, or emulsified, using stirrers,
agitators, or other dynamic mixing techniques, in one or more
solvents containing the wall forming material. Solvent is then
removed from the microparticles and thereafter the microparticle
product is obtained.
[0005] One variable that affects the in vitro and in vivo
performance of the microparticle product is the molecular weight of
the polymer or polymeric matrix material in the final microparticle
product Molecular weight affects drug release characteristics. The
molecular weight of a polymer influences the biodegradation rate of
the polymer. For a diffuisional mechanism of active agent release,
the polymer should remain intact until all of the active agent is
released from the microparticles, and then degrade. The active
agent can also be released from the microparticles as the polymeric
matrix material bioerodes. By an appropriate selection of polymeric
materials a microparticle formulation can be made in which the
resulting microparticles exhibit both diffusional release and
biodegradation release properties. This is useful in affording
multiphasic release patterns.
[0006] It has been reported that the molecular weight of the
poly(D,L-lactide) ("DL-PL") component of microcapsules containing
up to 50% thioridazine free base decreased during fabrication, and
in dissolution rate studies of the microcapsule (see Maulding, H.
V. et al, Biodegradable Microcapsules: "Acceleration of Polymeric
Excipient Hydrolytic Rate by Incorporation of a Basic Medicament".
Journal of Controlled Release. Volume 3, 1986, pages 103-117,
hereinafter "the Maulding article"). The results reported in the
Maulding article reveal that the degradation rate of DL-PL in
ketotifen free base microcapsules was greater when the
encapsulation process was carried out at 4.degree. C. than it was
when the encapsulation process was carried out at 25.degree. C. In
contrast, the degradation rate of DL-PL in thioridazine free base
microcapsules was greater when the encapsulation process was
carried out at 23.degree. C. than it was when the encapsulation
process is carried out at 4.degree. C. Based on these results, the
Maulding article suggests circumventing the polymer degradation by
carrying out the preparation of microcapsules at 4.degree. C. in
the case of thioridazine base. The Maulding article does not
provide a method by which the molecular weight of the polymer in
the finished microparticle can be conveniently controlled Nor does
the Maulding article provide a method for preparing microparticles
that have a selected polymer molecular weight in the finished
microparticle product.
[0007] Thus, there is a need in the art for an improved method for
preparing microparticles that controls the molecular weight of the
polymer or polymeric matrix material in the finished microparticle
product There is a particular need in the art for an improved
process that provides a method for preparing microparticles that
have a selected polymer molecular weight The present invention, the
description of which is fully set forth below, solves the need in
the art for such an improved method.
[0008] Summary of the Invention The present invention relates to a
method for preparing microparticles. The present invention allows
microparticle products of varying polymer molecular weights to be
produced using the same molecular weight starting material. The
present invention also allows microparticle products with
substantially the same polymer molecular weight to be produced from
starting materials of varying molecular weight. In one aspect of
the invention, a method of preparing microparticles having a
selected microparticle polymer molecular weight is provided. The
method comprises:
[0009] (a) preparing a first phase, the first phase comprising a
nucleophilic compound, a polymer having a starting molecular
weight, and a solvent for the polymer:
[0010] (b) combining the first phase with a second phase under the
influence of mixing means to form an emulsion.
[0011] (c) combining the emulsion and an extraction medium, thereby
forming microparticles; and
[0012] (d) maintaining the first phase at a hold temperature for a
hold period prior to step (b), the hold period of sufficient
duration to allow the starting molecular weight of the polymer to
reduce so that the selected microparticle polymer molecular weight
is achieved.
[0013] In a further aspect of the present invention, another method
for preparing microparticles is provided. The method comprises:
[0014] (a) providing a polymer having a starting molecular
weight;
[0015] (b) dissolving the polymer and a nucleophilic compound in a
solvent to form a first phase;
[0016] (c) combining the first phase with a second phase under the
influence of mixing means to form an emulsion;
[0017] (d) combining the emulsion and an extraction medium, thereby
forming microparticles: and
[0018] (e) maintaining the first phase at a hold temperature for a
hold period prior to step (c), wherein the hold period is selected
so that the starting molecular weight reduces so that a selected
microparticle polymer molecular weight is achieved.
[0019] In other aspects of the present invention, the foregoing
methods comprise adding an active agent to the first phase. In yet
further aspects of the present invention, the foregoing methods
comprise adding an inactive agent to the first phase.
[0020] In further aspects of the invention, the hold temperature is
increased, thereby increasing the molecular weight decay of the
polymer to reduce the duration of the hold period. The hold
temperature can be decreased, thereby decreasing the molecular
weight decay of the polymer to increase the duration of the hold
period.
[0021] Other aspects of the present invention include a
microencapsulated active agent and microparticles prepared by the
methods of the present invention.
[0022] Features and Advantages
[0023] It is a feature of the present invention that it can be used
to prepare microparticles, including microparticles containing an
active agent
[0024] It is a further feature of the present invention that it
allows the hold time and temperature of a nucleophilic
compound/polymer solution to be modified to achieve a selected
polymer molecular weight in the microparticle product.
[0025] An advantage of the present invention is that a selected
polymer molecular weight can be achieved in the microparticle
product by using a variety of polymers, having varying starting
molecular weights, by varying the hold time of the nucleophilic
compound/polymer solution.
[0026] A further advantage of the present invention is that
microparticle products of varying polymer molecular weights can be
produced using the same starting polymer, or using a polymer having
the same starting molecular weight
BRIEF DESCRIPTION OF THE FIGURES
[0027] The present invention is described with reference to the
accompanying drawings. In the drawings, like reference numbers
indicate identical or functionally similar elements.
[0028] FIG. 1 depicts a graph of molecular weight loss percentage
as a function of solution hold time (hours) at a 1 kg scale;
[0029] FIG. 2 depicts a graph of molecular weight loss percentage
as a function of solution hold time (hours) at a 20 kg scale;
[0030] FIG. 3 depicts a graph of molecular weight (kD) as a
function of solution hold time (hours) at 15.degree. C., 25.degree.
C. and 35.degree. C.; and
[0031] FIG. 4 shows one embodiment of an equipment configuration
suitable for preparing microparticles in accordance with the
present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0032] Overview
[0033] The present invention provides an improved method for
preparing microparticles. The methods of the present invention
control the hold time and temperature of a polymer solution in
order to control the molecular weight of the polymer in the
finished microparticle product. In this manner, the methods of the
present invention advantageously allow a selected polymer molecular
weight to be achieved from a variety of starting material molecular
weights. Alternatively, microparticle products of varying polymer
molecular weights can be produced using the same molecular weight
starting material. Thus, a range of products can be made from the
same starting materials. thereby eliminating the need to
reformulate the finished product to achieve the desired molecular
weight of the polymer in the finished product.
[0034] The polymer solution used in the present invention comprises
a nucleophilic compound. As used herein. "nucleophilic compound"
refers to a compound that promotes by nucleophilic catalysis the
ester hydrolysis, such as the polymer scission, that occurs in the
biodegradation of biodegradable polymers, such as polymers
comprising varying lacotide:glycolide ratios. A nucleophilic
compound is a more effective nucleophile toward an ester group of
the polymer than hydroxide ion or water. Nucleophilic compounds
that catalyze the polymer hydrolysis include, but are not limited
to, amines and carboxylate anions, and can be "active agents"
(defined below) or "inactive agents" that are not active agents.
Examples of nucleophilic compounds that are active agents include,
but are not limited to, risperidone, 9-hydroxyrisperidone, and
pharmaceutically acceptable salts of the foregoing, naltrexone, and
oxybutynin. Examples of nucleophilic compounds that are inactive
agents include, but are not limited to, protamine sulfate,
spermine, choline, ethanolamine, diethanolamine, and
triethanolamine. It should be readily apparent to be one skilled in
the art that the present invention is not limited to any particular
nucleophilic compound, and that the present invention encompasses
other nucleophilic active agents and nucleophilic inactive
agents.
[0035] To ensure clarity of the description that follows, the
following definitions are provided. By "microparticles" or
"microspheres" is meant particles that comprise a polymer that
serves as a matrix or binder of the particle. The microparticle may
contain an active agent or other substance dispersed or dissolved
within the polymeric matrix. The polymer is preferably
biodegradable and biocompatible. By "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 biodegradation should also be
biocompatible with the body. By "biocompatible" is meant not toxic
to the body, is pharmaceutically acceptable, is not carcinogenic,
and does not significantly induce inflammation in body tissues. As
used herein. "body" preferably refers to the human body, but it
should be understood that body can also refer to a non-human animal
is body. By "weight %" or "% by weight" is meant parts by weight
per total weight of microparticle. For example, 10 wt. % active
agent would mean 10 parts active agent by weight and 90 parts
polymer by weight. By "controlled release microparticle" or
"sustained release microparticle" is meant a microparticle from
which an active agent or other type of substance is released as a
function of time. By "mass median diameter" is meant the diameter
at which half of the distribution (volume percent) has a larger
diameter and half has a smaller diameter.
[0036] By "active agent" is meant an agent, drug, compound,
composition of matter or mixture thereof which provides some
pharmacologic, often beneficial, effect. This includes foods, food
supplements, nutrients, drugs, vitamins, and other beneficial
agents. As used herein, the terns further include any
physiologically and pharmacologically active substance that
produces a localized or systemic effect in a patient. Such active
agents include antibiotics, antiviral agents, anepileptics,
analgesics, anti-asthmatics. anti-inflammatory agents and
bronchodilators, and may be inorganic and organic compounds,
including, without limitation, drugs which act on the peripheral
nerves, adrenergic receptors, cholinergic receptors, the skeletal
muscles, the cardiovascular system, smooth muscles, the blood
circulatory system, synoptic sites, neuroeffector junctional sites.
endocrine and hormone systems, the immunological system, the
reproductive system, the skeletal system, autacoid systems, the
alimentary and excretory systems, the histamine system and the
central nervous system. Suitable agents may be selected from, for
example, polysaccharides, steroids, hypnotics and sedatives,
tranquilizers. anticonvulsants, muscle relaxants, antiParkinson
agents, analgesics, anti-inflammatories, muscle contractants,
antimicrobials, antimalarials, hormonal agents including
contraceptives, sympathomimetics, polypeptides and proteins capable
of eliciting physiological effects, diuretics, lipid regulating
agents, antiandrogenic agents, leukotriene antagonists,
antiparasites, neoplastics, antineoplastics, hypoglycemics,
nutritional agents and supplements, growth supplements, fats,
ophthalmics, antienteritis agents, electrolytes and diagnostic
agents.
[0037] Method and Examples
[0038] The following examples are provided to explain the
invention, and to describe the materials and methods used in
carrying out the invention. The examples are not intended to limit
the invention in any manner.
[0039] Molecular Weight Experiments with Nucleophilic Compounds
EXAMPLE 1
[0040] A series of experiments were conducted at the 1 kg scale
that demonstrate the relationship between molecular weight of the
finished microparticle product, and the duration of a hold period
of a nucleophilic compound/polymer solution. Microparticles
comprising risperidone were prepared at the one-kilogram scale. The
1 Kg process (400 grams of active agent and 600 grams of polymer)
provides a theoretical drug loading of the microparticles of 40%
(400 grams/1000 grams.times.100%).
[0041] A 16.7 wt. % polymer solution was prepared by dissolving 600
grams of MEDISORB.RTM. 7525 DL polymer (Alkermes, Inc., Blue Ash,
Ohio) in ethyl acetate. A 24 wt. % drug solution was prepared by
dissolving 400 grams of risperidone (basic nucleophilic active
agent) (Janssen Pharmaceutica, Beerse, Belgium) in benzyl alcohol.
A nucleophilic active agent/polymer solution (organic phase) was
prepared by mixing the drug solution into the polymer solution. The
active agent/polymer solution was maintained at a temperature of
25.+-.5.degree. C. The active agent/polymer solution is held for a
hold time of sufficient duration to achieve the selected or desired
polymer molecular weight in the finished microparticle product,
based on the starting molecular weight or the polymer. The results
of the experiments, showing the effect of hold time on molecular
weight loss, are discussed in more detail below with respect to
Table 1 and FIG. 1.
[0042] The second, continuous phase was prepared by preparing a 30
liter solution of 1% polyvinyl alcohol (PVA), the PVA acting as an
emulsifier. To this was added 2086 grams of ethyl acetate to form a
6.5 wt. % solution of ethyl acetate.
[0043] The two phases were combined using a static mixer, such as a
1/2' Kenics static mixer available from Chemineer, Inc., North
Andover, Mass. A total flow rate of 3 L/min generally provides
microparticle size distributions with a mass median diameter (MMD)
in the range of about 80-90.mu. The ratio of continuous phase to
discontinuous phase was 5:1 (v/v).
[0044] The quench liquid was 2.5% solution of ethyl acetate and
water-for-injection (WFI) at 5-10.degree. C. The volume of the
quench liquid is 0.25 L per gram of batch size. The quench step was
carried out for a time period greater than about 4 hours, with
stirring of the microparticles in the quench tank.
[0045] After completion of the quench step, the microparticles were
collected, de-watered, and dried. The temperature was maintained at
less than about 15.degree. C.
[0046] The microparticles were then re-slurried in a re-slurry tank
using a 25% ethanol solution. The temperature in the re-slurry tank
was in the range of about 0.degree. C. to about 15.degree. C. The
microparticles were then transferred back to the quench tank for
washing for a time period of at least 6 hours with another
extraction medium (25% ethanol solution) that was maintained at
preferably 25.degree..+-.10C.
[0047] The microparticles were collected, de-watered, and dried The
temperature was warmed to greater than about 20.degree. C. but
below 40.degree. C. Drying continued for a time period greater than
about 16 hours.
[0048] Twenty-four batches of risperidone microparticles at the 1
kg scale were prepared using the process described above. Table 1
below shows, for each batch, the starting molecular weight of the
polymer (kD), the final molecular weight of the polymer in the
finished microparticle product (kD), the percent loss in molecular
weight of the polymer. and the hold time (hours) of the active
agent/polymer solution. The molecular weight of the polymer in the
finished microparticle product was determined by GPC.
1TABLE 1 Starting Mw Final Mw Hold time Batch# kD kD % Loss Hours
825 230 182 21.0 0.10 708 161 110 32.0 2.08 714 161 133 17.3 0.33
812 161 100 37.9 2.40 819 161 102 36.7 2.47 319 131 110 16.2 0.10
331 131 115 12.2 0.07 423 131 78 40.7 2.85 506 129 112 13.6 0.07
512 129 86 33.7 3.10 520 129 92 29.1 3.07 527 129 95 26.8 2.22 603
129 65 49.4 6.10 610 129 101 22.0 1.13 617 128 95 26.1 2.20 902 128
85 33.8 1.90 908 128 91 29.0 1.18 921 128 99 23.2 0.08 930 128 103
19.4 0.03 915 92 69 24.8 1.82 1021 135 104 23.0 0.03 1028 138 119
13.7 0.45 1110 138 115 16.8 1.28 1215 138 111 19.4 1.50
[0049] The data reported in Table 1 is depicted in the graph shown
in FIG. 1. FIG. 1 to shows an initial loss in molecular weight of
approximately 17%, with an additional loss of approximately 5.7%
per hour of hold time of the active agent/polymer solution.
EXAMPLE 2
[0050] Additional experiments were conducted at the 20 kg scale
that also demonstrate the relationship between molecular weight of
the finished microparticle product, and the duration of a hold
period of a nucleophilic compound/polymer solution. Microparticles
comprising risperidone were prepared at the twenty-kilogram scale.
The 20 Kg process (8 kg of active agent and 12 kg of polymer)
provides a theoretical drug loading of the microparticles of 40% (8
kg/20 kg.times.100%).
[0051] A 16.7 wt. % polymer solution was prepared by dissolving 12
kg of MEDISORB.RTM. 7525 DL polymer (Alkermes, Inc., Blue Ash,
Ohio) in ethyl acetate. A 24 wt. % drug solution was prepared by
dissolving 8 kg of risperidone (Janssen Pharmaceutica, Beerse.
Belgium) in benzyl alcohol. A nucleophilic active agent/polymer
solution (organic phase) was prepared by mixing the drug solution
into the polymer solution. The active agent/polymer solution was
maintained at a temperature of 25.+-.5.degree. C. The active
agent/polymer solution is held for a hold time of sufficient
duration to achieve the selected or desired polymer molecular
weight in the finished microparticle product, based on the starting
molecular weight of the polymer. The results of the experiments.,
showing the effect of hold time on molecular weight loss. are
discussed in more detail below with respect to Table 2 and FIG.
2.
[0052] The second, continuous phase was prepared by preparing a 600
liter solution of 1% PVA, the PVA acting as an emulsifier. To this
was added 42 kg of ethyl acetate to form a 6.5 wt. % solution of
ethyl acetate. The two phases were combined using a static mixer,
such as a 1" Kenics static mixer available from Chemineer. Inc.,
North Andover. Mass.
[0053] The quench liquid was 2.5% solution of ethyl acetate and
water-for-injection (WFI) at 5-10.degree. C. The volume of the
quench liquid is 0.25 L per gram of batch size. The quench step was
carried out for a time period greater than about 4 hours, with
stirring of the microparticles in the quench tank.
[0054] After completion of the quench step, the microparticles were
collected, de-watered, and dried. The temperature was maintained at
less than about 15.degree. C.
[0055] The microparticles were then re-slurried in a re-slurry tank
using a 25% ethanol solution. The temperature in the re-slurry tank
was in the range of about 0.degree. C. to about 15.degree. C. The
microparticles were then transferred back to the quench tank for
washing for a time period of at least 6 hours with another
extraction medium (25% ethanol solution) that was maintained at
preferably 25.+-.1.degree. C.
[0056] The microparticles were collected de-watered, and dried. The
temperature was warmed to greater than about 20.degree. C. but
below 40.degree. C. Drying continued for a time period greater than
about 16 hours.
[0057] Four batches of risperidone microparticles at the 20 kg
scale were prepared using the process described above. Table 2
below shows, for each batch, the starting molecular weight of the
polymer (kD), the final molecular weight of the polymer in the
finished microparticle product (kD), the percent loss in molecular
weight of the polymer, and the hold time (hours) of the active
agent/polymer solution. The molecular weight of the polymer in the
finished microparticle product was determined by GPC.
2 Starting Mw Final Mw Hold time Batch# kD kD % Loss hours 3308 146
117 20 0.5 4068 145 103 29 1.75 4138 143 111 22 1.0 4208 143 110 23
1.0
[0058] The data reported in Table 2 show that from a relatively
constant molecular weight starting material (143 kD, 145 kD, and
146 kD), a variable finished microparticle product molecular weight
was achieved by varying the hold time of the active agent/polymer
solution hold time. The data reported in Table 2 is depicted in the
graph shown in FIG. 2. FIG. 2 shows an initial loss in molecular
weight of approximately 16%, with an additional loss of
approximately 7.3% per hour of hold time of the active
agent/polymer solution.
EXAMPLE 3
[0059] The starting molecular weight of the polymer (kD) and the
final molecular weight of the polymer in a finished microparticle
product (kD) was determined for microparticles containing the
nucleophilic compound naltrexone. The starting polymer
lactide:glycolide ratio was 75:25, 85:15, and 65:35. The polymers
used were MEDISORB.RTM. 7525 DL polymer, MEDISORB.RTM. 8515 DL
polymer and MEDISORB.RTM. 6535 DL polymer, all available from
Alkermes, inc. Blue Ash. Ohio.
[0060] The naltrexone base microparticles were produced using a
co-solvent extraction process. The theoretical batch size was 15 to
20 grams. The polymer was dissolved in to ethyl acetate to produce
a 16.7% w/w polymer solution. The naltrexone base anhydrous was
dissolved in benzyl alcohol to produce a 30.0% w/w solution. In
various batches, the amount of drug and polymer used was varied to
produce microparticles with different theoretical drug loading
ranging from 30% -75%. The ambient polymer and drug solutions were
mixed together until a single homogeneous solution (organic phase)
was produced. The aqueous phase was at ambient conditions and
contained 1% w/w polyvinyl alcohol and a saturating amount of ethyl
acetate. These two solutions were pumped via positive displacement
pumps at a ratio of 3:1 (aqueous:organic) through a 1/4" in-line
mixer to form an emulsion. The emulsion was transferred to a
stirring solvent extraction solution consisting of 2.5% w/w of
ethyl acetate dissolved in distilled water at 5-10.degree. C. and
at a volume of 0.5 L of extraction solution per theoretical gram of
microparticles. Both the polymer and drug solvents were extracted
into the extraction solution from the emulsion droplets to produce
microparticles. The initial extraction process ranged from two to
four hours. The microparticles were collected on a 25 .mu.m sieve
and rinsed with a cold (<5.degree. C.) 25% w/w ethanol solution.
The microparticles were dried cold overnight (approximately 17
hours) using nitrogen. The microparticles were then transferred to
the reslurry solution, which consisted of a vigorously stirring 25%
w/w ethanol solution at 5-10.degree. C. After a short mixing time
(five to fifteen minutes). the reslurry solution and the
microparticles were transferred to a stirring 25% w/w ethanol
secondary extraction solution (approximately 25" C. at a volume of
0.2 L of secondary extraction solution per theoretical gram of
microparticles). The microparticles stirred for six hours enabling
additional solvent removal from the microparticles to take place.
The microparticles were then collected on a 25 .mu.m sieve and
rinsed with a 25% w/w ethanol solution at ambient temperature.
These microparticles dried in a hood under ambient conditions
overnight (approximately 17 hours), were sieved to remove
agglomerated microparticles and then placed into a freezer for
storage.
[0061] As shown below in Table 3. three batches of microparticles
were prepared using the 75:25 polymer, two batches for the 85:15
polymer, and four batches for the 65:35 polymer. For each batch.
Table 3 shows the starting molecular weight of the polymer (kD),
and the final molecular weight of the polymer in the finished
microparticle products (kD), and the percent loss in molecular
weight of the polymer. The molecular weight of the polymer in the
finished microparticle product was determined by GPC. The data in
Table 3 provides an example of the loss in molecular weight of the
polymer in a finished microparticle product containing a
nucleophilic compound (naltrexone) for polymers having varying
lactide:glycolide ratios.
3TABLE 3 Starting Polymer Starting Mw Final Mw Lactide:glycolide
ratio Batch kD kD % Loss 75:25 99-123-004 116.2 76.0 34.6
99-123-009 116.2 74.0 36.3 99-123-012 116.2 74.3 36.1 85:15
99-123-016 109.7 83.7 23.7 99-123-024 109.7 74.9 31.7 65:35
99-123-021 102.3 56.3 45.0 99-123-028 102.3 63.4 38.0 99-123-037
102.3 69.6 32.0 99-123-034 102.3 79.6 22.2
EXAMPLE 4
[0062] Additional experiments were conducted with other polymers
that also demonstrate the relationship between molecular weight of
the finished microparticle product, and the duration of a hold
period of a nucleophilic compound/polymer solution. Microparticles
comprising other polymers having different lactide:glycolide ratios
were prepared. Microparticles comprising risperidone using polymers
having lactide:glycolide ratios of 65:35, 85:15, and 100:0 were
prepared at the 1 Kg scale using the same process described above
in Example 1. The polymers used were MEDISORB.RTM. 6535 DL polymer,
MEDISORB.RTM. 8515 DL polymer, and MEDISORB.RTM. 100 DL polymer,
all available from Alkermes, Inc., Blue Ash. Ohio.
[0063] Table 4 below shows, for each polymer, the starting
molecular weight of the polymer (kD), the final molecular weight of
the polymer in the finished microparticle product (kD), the percent
loss in molecular weight of the polymer, and the hold time (hours)
of the active agent/polymer solution. The molecular weight of the
polymer in the finished microparticle product was determined by
GPC.
4TABLE 4 Lactide:glycolide Starting Mw Final Mw Hold time ratio kD
kD % Loss hours 65:35 105 79 24.8 0.27 85:15 112 96 14.3 0.23 100
dl 105 98 6.7 0.17
[0064] The data reported in Table 4 show that a microparticle
product having about the same molecular weight (96 kD and 98 kD)
can be prepared from two different molecular weight polymers (112
kD and 105 kD, respectively) having two different lactide:glycolide
ratios (85:15 and 100:0, respectively). The present invention thus
advantageously allows microparticle products with the same polymer
molecular weight to be produced using two different starting
materials.
EXAMPLE 5
[0065] Additional experiments were conducted that demonstrate the
molecular weight loss of polymers in the presence of a nucleophilic
compound (oxybutynin) as a function of time. Tests were conducted
using a 100:0 lactide:glycolide polymer and two 75:25
lactide:glycolide polymers with differing inherent viscosity. For
each test, the following protocol was carried out. Weigh about 6 g
polymer into an Erlenmeyer flask. Add to the polymer 44 g ethyl
acetate, sonicate and shake to dissolve the polymer. Weigh 1.5 g
oxybutynin base. Stir the polymer solution, and add the drug to the
polymer solution. Start the timer as the drug is added. Sample the
drug/polymer solution at 1, 5 and 15 minutes, taking about 1/3 of
the original volume for each aliquot as the solution stirs.
Dispense the aliquot into 250 mL 50:50 H.sub.2O:MeOH, and stir.
This mix precipitates the polymer and removes the drug from the
precipitate. Allow precipitated polymer to settle and decant the
supernatant Wash polymer residue with 100 mL MeOH, stir
approximately one minute, add up to 250 mL H.sub.2O. Allow polymer
to settle again, and repeat Residue is then removed from the beaker
and placed in a scintillation vial and frozen. Once all samples are
collected and frozen, all samples are placed in a lyophilizer,
cooled to -10.degree. C. The lyophilizer is activated, and once a
stable vacuum is achieved, the shelf temperature is raised to
15.degree. C. and held overnight (.about.18 hours) to remove
residual solvents.
[0066] The results of these experiments are shown in Table 5. For
each experiment, the starting molecular weight of the polymer is
shown, along with the polymer molecular weight at 1, 5, and 15
minutes of exposure of the polymer to the nucleophilic compound in
the drug/polymer solution. As can be seen in Table 5. the longer
the exposure or hold time of the drug/polymer solution, the lower
the molecular weight of the polymer.
5TABLE 5 Starting Polymer Time = Lactide:glycolide Starting Time =
1 min Time = 5 min 15 min ratio Mw, kD Mw, kD Mw, kD Mw, kD 100:0
77.1 67.2 63 60.8 75:25 82.8 56.2 55.1 48.8 75:25 54.1 44.1 42.9
38.4
[0067] Molecular Weight Temperature Experiments
EXAMPLE 6
[0068] Additional experiments were conducted to determine the
effect of temperature on the relationship between molecular weight
of the finished microparticle product, and the duration of a hold
period of a nucleophilic compound/polymer solution. Fifty grams of
risperidone (Janssen Pharmaceutica, Beerse, Belgium) were dissolved
in 275 g of benzyl alcohol to form a drug solution. A polymer
solution was formed by dissolving 75 g of to MEDISORB.RTM. 7525 DL
polymer (Alkermes, Inc., Blue Ash, Ohio) in ethyl acetate. The
starting molecular weight of the polymer was 146 kD. The drug
solution and the polymer solution were mixed to form a combined
solution. A flask of the combined solution was placed in each of a
15.degree. C. 25.degree. C., and 35.degree. C. chamber. At periodic
time intervals, 10 cc of the combined solution was withdrawn from
the flask in each chamber via a syringe and needle. The 10 cc
sample was then precipitated in a bath containing 200 ml methanol
at room temperature (approximately 20.degree. C.). The polymeric
precipitate was recovered from the methanol bath, and vacuum dried
overnight The dried samples were tested for their molecular weight
by GPC.
[0069] The results of the experiments are depicted in the graph of
FIG. 3. As shown in FIG. 3, the molecular weight decay increases as
temperature increases. Therefore, by increasing the hold
temperature of the solution containing the polymer and the
nucleophilic compound, the molecular weight decay of the polymer
increases, and the duration of the hold period to achieve a
particular molecular weight reduction is reduced. Similarly, by
decreasing the hold temperature of the solution containing the
polymer and the nucleophilic compound, the molecular weight decay
of the polymer decreases. and the duration of the hold period to
achieve a particular molecular weight reduction is increased. For
example, the time required to reduce the molecular weight form 130
kD to 110 kD is the shortest at 35.degree. C. (about 5 hours) and
the longest at 15.degree. C. (about 15 hours).
[0070] FIG. 3 shows an initial increase in polymer molecular
weight. This phenomenon is most likely occurring because some
portion of the polymer, particularly the lower molecular weight
fractions is soluble in the extraction medium. Because the
analytical measurement of molecular weight is a representation of
all the molecular weight fractions present, removing (dissolving)
the low molecular weight material can increase the measured
molecular weight.
[0071] Methods of Preparing Microparticles
EXAMPLE 7
[0072] As exemplified by the examples discussed above, methods for
preparing microparticles having a selected microparticle polymer
molecular weight in accordance with the present invention will now
be described in more detail. In one embodiment of the present
invention, a first phase, comprising a nucleophilic compound, a
polymer having a starting molecular weight, and a solvent for the
polymer, is prepared. In one embodiment of the present invention,
the first phase is prepared by dissolving a nucleophilic active
agent in a first solvent to form an active agent solution. The
polymer is dissolved in a second solvent to form a polymer
solution. The active agent solution and the polymer solution are
blended to form the first phase. In a particularly preferred
embodiment, the active agent is selected from the group consisting
of risperidone. 9-hydroxyrisperidone, and pharmaceutically
acceptable salts thereof. In such an embodiment, a preferred first
solvent is benzyl alcohol, and a preferred second solvent is ethyl
acetate.
[0073] In another embodiment of the present invention, the first
phase is prepared by dissolving the nucleophilic compound and the
polymer in a solvent to form a solution. In yet a further
embodiment, an active agent is added to the first phase. In a
further embodiment, an inactive agent is added to the first phase.
It should be understood that the present invention is not limited
to any particular method or process by which the first phase is
prepared, and other suitable processes would be readily apparent to
one skilled in the art.
[0074] A second phase is prepared, and combined with the first
phase under the influence of mixing means to form an emulsion. In a
preferred embodiment, a static mixer is used to combine the two
phases to form an emulsion. A process for forming an emulsion using
a static mixer is described, for example, in U.S. Pat. No.
5,654,008, the entirety of which is incorporated herein by
reference. The emulsion is combined with an extraction medium that
extracts solvent from the emulsion droplets, thereby hardening them
into microparticles.
[0075] Prior to combining the first and second phases, the first
phase is maintained at a hold temperature for a hold period. The
hold period is of sufficient duration to allow the a5 starting
molecular weight of the polymer to reduce to the selected
microparticle polymer molecular weight at the hold temperature.
Based on the teachings and examples provided herein, and the
knowledge of skilled artisans, the determination of suitable hold
temperatures and hold periods is within the routine skill of
skilled artisans and would not require undue experimentation. In a
preferred embodiment of the present invention, the starting
molecular weight of the polymer reduces by about 10% to about 50%
to reach the selected polymer molecular weight However, it should
be understood by one skilled in the art that the present invention
is not limited to such a percentage reduction.
[0076] During the hold period, the first phase may be mixed,
stirred, or otherwise agitated. Alternatively, during the hold
period, the first phase may be subjected to no mixing, stirring, or
agitation. The hold temperature is preferably in the range of from
about 15.degree. C. to about 35.degree. C. more preferably about
25.degree. C.
[0077] An alternate method for preparing microparticles in
accordance with the present invention will now be described. A
polymer having a starting-molecular weight and a nucleophilic
compound are dissolved in a solvent to form a first phase. An
active agent and/or an inactive agent can be added to the first
phase. The first phase is combined with a second phase under the
influence of mixing means to form an emulsion. The emulsion is
combined with an extraction medium that extracts solvent, thereby
hardening the emulsion droplets into microparticles. Prior to
combining the first and second phases, the first phase is
maintained at a hold temperature for a hold period. The hold period
is selected so that the starting molecular weight of the polymer
reduces to a selected microparticle polymer molecular weight at the
hold temperature. The duration of the hold period can be adjusted
by changing the hold temperature in a manner as described
above.
[0078] Microparticles of the Present Invention
[0079] The microparticles prepared by the process of the present
invention preferably comprise a polymeric binder. Suitable
polymeric binder materials include poly(glycolic acid),
poly-d,l-lactic acid, poly-l-lactic acid, copolymers of the
foregoing, poly(aliphatic carboxylic acids), copolyoxalates,
polycaprolactone, polydioxanone, poly(ortho carbonates),
poly(acetals), poly(lactic acid-caprolactone), polyorthoesters,
poly(glycolic acid-caprolactone), polyanhydrides, and
polyphosphazines. Poly (d,l-lactic-co-glycolic acid) is
commercially available from Alkermes, Inc. (Blue Ash, Ohio). A
suitable product commercially available from Alkermes, Inc. is a
50:50 poly(d,l-lactic-co-glycolic acid) known as MEDISORB.RTM. 5050
DL. This product has a mole percent composition of 50% lactide and
50% glycolide. Other suitable commercially available products are
MEDISORB.RTM. 6535 DL, 7525 DL 8515 DL and poly(d,l-lactic acid)
(100 DL).
[0080] Poly(lactide-co-glycolides) are also commercially available
from Boehringer Ingelheim (Germany) under its Resomer.RTM. mark.
e.g., PLGA 50:50 (Resome.RTM. RG 502), PLGA 75:25 (Resome.RTM. RG
752) and d,l-PLA (Resomer.RTM. RG 206), and from Birmingham
Polymers (Birmingham, Ala.). These copolymers are available in a
wide range of molecular weights and ratios of lactic acid to
glycolic acid.
[0081] One type of microparticle suitable for preparation by the
present invention is a sustained-release microparticle that is
biodegradable. However, it should be understood by one skilled in
the art that the present invention is not limited to biodegradable
or other types of sustained-release microparticles. As would be
apparent to one skilled in the art, the molecular weight of the
polymeric binder material for biodegradable microparticles 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. However, since the properties
of the film are also partially dependent on the particular
polymeric binder material being used, it- is very difficult to
specify an appropriate molecular weight range for all polymers. The
molecular weight of the 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 binder 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 according multiphasic release
patterns. A satisfactory starting molecular weight of the polymer
is in the range of 5-500 kD, preferably in the range of from about
50 kD to about 250 kD. The microparticle polymer molecular weight
is preferably in the range of from about 10 kD to about 185 kD.
[0082] The microparticles prepared in accordance with the present
invention may include an active agent or other type of substance
that is released from the microparticles into the host. However, it
should be understood that the present invention is not limited to
preparation of microparticles that contain an active agent The
active agent can be a nucleophilic compound. Alternatively, the
active agent is not a nucleophilic compound and is added to the
microparticles during the formation process. Such active agents can
include 1,2-benzazoles, more particularly,
3-piperidinyl-substituted 1,2-benzisoxazoles and
1,2-benzisothiazoles. The most preferred active agents of this kind
are 3-[2-[4-(6-fluoro
1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tet-
rahydro-2-methy4H--pyrido[1,2-a]pyrimidin-4-one ("risperidone") and
3-[2-[4-(6-fluro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetr-
ahydro-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.
Risperidone can be prepared in accordance with the teachings of
U.S. Pat. No. 4,804,663, the entirety of which is incorporated
herein by reference. 9-hydroxyrisperidone can be prepared in
accordance with the teachings of U.S. Pat. No. 5,158,952, the
entirety of which is incorporated herein by reference.
[0083] Other biologically active agents include non-steroidal
antifertility agents:. parasympathomimetic agents;
psychotherapeutic agents; tranquilizers; decongestants; sedative
hypnotics; steroids; sulfonamides; sympathomimetic agents;
vaccines; vitamins; antimalarials; anti-migraine agents;
anti-Parkinson agents such as L-dopa; anti-spasmodics;
anticholinergic agents (e.g. oxybutynin); antitussives;
bronchodilators; cardiovascular agents such as coronary
vasodilators and nitroglycerin; alkaloids; analgesics; narcotics
such as codeine, dihydrocodienone, meperidine, morphine and the
like; non-narcotics such as salicylates, aspirin, acetaminophen,
d-propoxyphene and the like; opioid receptor antagonists, such as
naltrexone and naloxone; antibiotics such as gentamycin,
tetracycline and penicillins; anti-cancer agents; anti-convulsants;
anti-emetics; antihistamines; anti-inflammatory agents such as
hormonal agents, hydrocortisone, prednisolone, prednisone,
non-hormonal agents, allopurinol, indomethacin, phenylbutazone and
the like; prostaglandins and cytotoxic drugs.
[0084] Still other suitable active agents include estrogens,
antibacterials; antifungals; antivirals; anticoagulants:
anticonvulsants; antidepressants; antihistanines; and immunological
agents.
[0085] Other examples of suitable biologically active agents
include peptides and proteins, analogs, muteins, and active
fragments thereof, such as immunoglobulins, antibodies, cytokines
(e.g. lymphokines, monokines, chemokines), blood clotting factors,
hemopoietic factors, interleukins (IL-2, IL-3, IL4, IL-6),
interferons (.beta.-IFN. .alpha.-IFN and .gamma.-IFN),
erythropoietin, nucleases, tumor necrosis factor, colony
stimulating factors (e.g., GCSF, GM-CSF, MCSF), insulin, enzymes
(e.g., superoxide dismutase, tissue plasminogen activator), tumor
suppressors, blood proteins, hormones and hormone analogs (e.g.,
growth hormone, adrenocorticotropic hormone and luteinizing hormone
releasing hormone (LURH)), vaccines (e.g., tumoral, bacterial and
viral antigens); somatostatin; antigens; blood coagulation factors;
growth factors (e.g., nerve growth factor, insulin-like growth
factor), protein inhibitors, protein antagonists, and protein
agonists; nucleic acids, such as antisense molecules;
oligonucleotides; and ribozymes. Small molecular weight agents
suitable for use in the invention include, antitumor agents such as
bleomycin hydrochloride, carboplatin, methotrexate and adriamycin;
antipyretic and analgesic agents; antitussives and expectorants
such as ephedrine hydrochloride, methylephedrine hydrochloride,
noscapine hydrochloride and codeine phosphate; sedatives such as
chlorpromazine hydrochloride, prochlorperazine hydrochloride and
atropine sulfate; muscle relaxants such as tubocurarine chloride;
antiepileptics such as sodium phenytoin and ethosuximide; antiulcer
agents such as metoclopramide; antidepressants such as
clomipramine; antiallergic agents such as diphenhydramine;
cardiotonics such as theophillol; antiarrhythmic agents such as
propranolol hydrochloride; vasodilators such as diltiazem
hydrochloride and bamethan sulfate; hypotensive diuretics such as
pentolinium and ecarazine hydrochloride; antidiuretic agents such
as metformin; anticoagulants such as sodium citrate and heparin;
hemostatic agents such as thrombin, menadione sodium bisulfite and
acetomenaphthone; antituberculous agents such as isoniazide and
ethanbutol; hormones such as prednisolone sodium phosphate and
methimazole.
[0086] The microparticles can be mixed by size or by type. However,
it should be understood that the present invention is not limited
to the use of biodegradable or other types of microparticles that
contain an active agent In one embodiment, the microparticles are
mixed in a manner that provides for the delivery of active agent to
the host in a multiphasic manner and/or in a manner that provides
different active agents to the host 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 host.
[0087] With reference now to FIG. 4, one embodiment is shown of an
equipment configuration suitable for use in preparing
microparticles in accordance with the present invention, in a
preferred embodiment of the present invention, the equipment
contained within the dotted line boundary shown generally at 270 is
sterilized using a "steam-in-place" (SIP) process.
[0088] A first phase 201 is provided. First phase 201 is preferably
the discontinuous phase, comprising a polymer dissolved in one or
more solvents, and an active agent. The active agent can be
dissolved or dispersed in the same or a different solvent than the
solvent(s) in which the polymer is dissolved. A second phase 202 is
preferably the continuous phase, preferably comprising water as the
continuous processing medium. Preferably, an emulsifying agent such
as a surfactant or a hydrophilic colloid is added to the continuous
phase to prevent the microdroplets from agglomerating and to
control the size of the 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) (PVA),
carboxymethyl cellulose, gelatin, poly(vinyl pyrrolidone), Tween
80, Tween 20, and the like. The concentration of surfactant or
hydrophilic colloid in the continuous phase will be from about 0.1%
to about 10% by weight based on the continuous processing mediums
depending upon the surfactant, hydrophilic colloid, the
discontinuous phase, and the continuous processing medium used. A
preferred continuous phase is 0.1 to 10 wt. %, more preferably 0.5
to 2 wt. %. solution of PVA in water. Although not absolutely
necessary, it is preferred to saturate the continuous phase with at
least one of the solvents forming the discontinuous phase.
[0089] First phase 201 and second phase 202 are combined under the
influence of mixing means to form an emulsion. A preferred type of
mixing means is a static mixer 210.
[0090] Other mixing means suitable for use with the present
invention include, but are not limited to, devices for mechanically
agitating the fist and second phases, such as homogenizers,
propellers, impellers, stirrers, and the like.
[0091] Preferably, the discontinuous and continuous phases 201 and
202 are pumped through static mixer 210 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. A pump 203 pumps first phase 201 into static mixer 210,
and a pump 204 pumps second phase 202 into static mixer 210. An
especially preferred method of mixing with a static mixer in the
process of the present invention is disclosed in U.S. Pat. No.
5,654,008, the entirety of which is incorporated herein by
reference.
[0092] First and second phases 201 and 202 are mixed in static
mixer 210 to form an emulsion. The emulsion formed comprises
microparticles containing active agent encapsulated in the
polymeric matrix material. The microparticles are then preferably
stirred in a quench or extraction tank 220, containing a quench
liquid in order to remove most of the solvent from the
microparticles, resulting in the formation of hardened
microparticles. Following the movement of the microparticles from
static mixer 210 and entrance into quench tank 220, the continuous
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 (second phase 202) used during emulsification, with or
without hydrophilic colloid or surfactant, or in another quench
liquid. The quench liquid removes a significant portion of the
solvent from the microparticles, but does not dissolve them. During
the extractive quench step, the quench liquid containing dissolved
solvent can, optionally, be removed and replaced with fresh quench
liquid.
[0093] Upon completion of the quench step in quench tank 220, the
microparticles are transferred by a pump 224 to a device 230 that
functions as a microparticle collecting device, de-watering device,
and drying device. Device 230 comprises a vibrating sieve or
screen. The vibration causes smaller particles and liquid to drop
through the screen, while larger particles are retained. The
smaller particles and liquid that drop through the screen are
removed as waste 235.
[0094] Device 230 also functions as a vacuum dryer, through the use
of a vacuum line 237. The microparticles are fluidized by the
vibrational energy, and by a small amount of a dry gas bleed,
preferably a dry nitrogen (N.sub.2) bleed 236.
[0095] The dried microparticles are transferred to another
extraction medium to carry out a wash step. The wash step is
preferably carried out in quench tank 220, using an extraction
medium 222 having a temperature higher than the glass transition
temperature (T.sub.g) of the microparticles. To carry out the wash
step, the microparticles are First introduced into a re-slurry tank
or other type of vessel 240, as shown by path 231. The temperature
of the extraction medium 242 that is used in vessel 240 is lower
than the T.sub.g of the microparticles.
[0096] After the wash step is completed in quench tank 220, the
microparticles are again transferred via pump 224 into device 230
for de-watering and final drying. At the completion of final
drying, the microparticles are discharged from device 230 in the
manner described above into a sifter 250, as shown by path 232.
Sifter 250 is used to fractionate the microparticles by size for
filling into vials and for bulk in-process testing (e.g., aspect,
active agent content, residual solvents, in vitro release, and
particle size distribution).
[0097] Conclusion
[0098] 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. The present
invention is not limited to the preparation of controlled release
microparticles or microparticles containing an active agent, nor is
it limited to a particular active agent, polymer or solvent, nor is
the present invention limited to a particular scale or batch size.
Thus, the breadth and scope of the present invention should not be
limited by any of the abovedescribed exemplary embodiments, but
should be defined only in accordance with the following claims and
their equivalents.
* * * * *