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Title: Pharmaceutical
preparation for the treatment of gynecological diseases
United States Patent: 7,041,310
Issued: May 9, 2006
Inventors: Yui; Nobuhiko
(4-103, Matsugaoka, Tatsunokuchi-machi, Nomi-gun, Ishikawa-ken, JP);
Murakami; Kouichi (Kanazawa, JP); Ooya; Tooru (Tsurugi-machi, JP); Sato;
Ikuo (Yokohama, JP)
Assignee: Chisso
Corporation (Osaka, JP); Yui; Nobuhiko (Ishikawa-ken, JP)
Appl. No.: 108298
Filed: March 28, 2002
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Training Courses -- Pharm/Biotech/etc.
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Abstract
This invention provides to a novel
pharmaceutical preparation for the treatment of gynecological diseases.
The pharmaceutical preparation according to the invention comprises a
therapeutic drug for the intrauterine, intravaginal or intrapelvic
administration, or for the administration into the ovarian endometrioma,
and a biodegradable polymer comprising a chemically modified hyaluronic
acid or a salt thereof prepared by O-acylating, alkoxylating or
crosslinking a complex of hyaluronic acid or a salt thereof and a cationic
compound in a nonaqueous solvent. The preparation of the invention is
preferably administered intrauterine, intravaginal, intrapelvic, and
intratumor cavity.
DISCLOSURE OF THE
INVENTION
An object of the present invention is to
provide a pharmaceutical preparation for the treatment of gynecological
diseases, wherein a carrier has a superior sustained releasing property of
a drug to be administered and needs not to be removed from the uterus
after the treatment. Another object of the invention is to provide use of
a carrier for manufacturing the pharmaceutical preparation for the
treatment of gynecological diseases.
We have intensively studied the aforementioned problems of the prior art
and found that a therapeutic drug for the intrauterine, intravaginal or
intrapelvic administration, or for the administration into the ovarian
endometrioma is effectively released from a pharmaceutical preparation
wherein the drug is supported by the biodegradable polymer as a carrier,
especially hyaluronic acid or a salt thereof.
We also found that a chemically modified hyaluronic acid or a salt thereof
prepared by O-acylating, alkoxylating or crosslinking a complex of
hyaluronic acid or a salt thereof and a cationic compound in a nonaqueous
solvent maintains a superior sustained releasing property of a drug in the
body for a long term. Furthermore, a carrier comprising the chemically
modified hyaluronic acid or a salt thereof according to the present
invention contains a reduced amount of a pyrogen and an antigenic
substance. Thus, there is concern with an adverse effect and its safety is
ensured.
If the pharmaceutical preparation according to the invention is directed
to the intrauterine, intravaginal or intrapelvic administration or the
administration into the ovarian endometrioma, a carrier according to the
invention needs not be removed from the uterus after the completion of the
release of the drug and thus physical and mental burden of patients are
significantly decreased.
In consideration of the above, we complete a pharmaceutical preparation
for the insertion into the uterine cavity or vagina, which has a superior
sustained releasing property of a therapeutic drug for the treatment of
gynecological diseases.
The present invention are defined in the following items (1) to (18).
(1) A pharmaceutical preparation for the treatment of gynecological
diseases which comprises a therapeutic drug for the intrauterine,
intravaginal or intrapelvic administration, or for the administration into
the ovarian endometrioma and a biodegradable polymer comprising hyaluronic
acid or a salt thereof and wherein the drug is supported by the
biodegradable polymer as a carrier.
(2) The pharmaceutical preparation as defined in item (1), in which the
biodegradable polymer is a chemically modified hyaluronic acid or a salt
thereof.
(3) The pharmaceutical preparation as defined in item (1), in which the
biodegradable polymer is a chemically modified hyaluronic acid or a salt
thereof prepared by O-acylating, alkoxylating or crosslinking a complex of
hyaluronic acid or a salt thereof and a cationic compound in a nonaqueous
solvent.
(4) The pharmaceutical preparation as defined in item (3), in which the
cationic compound is a quaternary ammonium salt.
(5) The pharmaceutical preparation as defined in item (3), in which the
nonaqueous solvent is one or more solvents selected from the group
consisting of chloroform, toluene, methylene chloride and heptane.
(6) The pharmaceutical preparation as defined in item (3), wherein an
amount of a pyrogen and/or an antigenic substance in the chemically
modified hyaluronic acid or a salt thereof is decreased by O-acylating,
alkoxylating or crosslinking the complex in the nonaqueous solvent.
(7) The pharmaceutical preparation as defined in item (6), wherein the
amount of the pyrogen is not more than 0.05 endotoxin unit (EU)/mg.
(8) The pharmaceutical preparation as defined in item (1), in which the O-acylating
reaction for the production of the biodegradable polymer is a reaction
with an organic acid employing at least one acid catalyst selected from
the group consisting of mineral acids, organic acids and Lewis acids, a
reaction with an organic acid employing at least one dehydrating agent
selected from the group consisting of N,N′-dicyclohexylcarbodiimide,
2-chloro-1-methyl pyridiniumiodide and N,N′-carbonyl diimidazole, or an O-acylation
employing an acid anhydride or an acid halide in the presence of an acid
binder.
(9) The pharmaceutical preparation as defined in item (1), in which the
alkoxylating reaction for the production of the biodegradable polymer is
an alkoxylation using an alkyl halide or an alkoxide in the presence of an
acid binder, or an alkoxylation by the dehydration of hydroxyl groups
using Brönsted acid or Lewis acid as an acid catalyst.
(10) The pharmaceutical preparation as defined in item (1), in which the
crosslinking reaction comprises irradiating a certain wavelength of light
to the chemically modified hyaluronic acid or a salt thereof into which a
photoreactive group has been introduced.
(11) The pharmaceutical preparation as defined in item (1), in which the
crosslinking reaction is an auto-crosslinking reaction using no
crosslinking agent or a reaction using at least one crosslinking agent
selected from the group consisting of polyfunctional aldehydes,
polyfunctional epoxy compounds and polyhydric alcohols.
(12) The pharmaceutical preparation as defined in item (1), wherein a
weight ratio of the drug to the biodegradable polymer is in the range of
1:10 to 2:1.
(13) The pharmaceutical preparation as defined in item (1), which is a
T-shaped preparation and wherein a vertical bar has a length of 20 to 40
mm and a diameter of 1.0 to 3.0 mm and wherein a transverse bar has a
length of 25 to 45 mm and a diameter of 3.0 to 4.0 mm.
(14) The pharmaceutical preparation as defined in item (1), which is a
IUD-like ring preparation and wherein an outside diameter is in the range
of 20 to 40 mm and a thickness is in the range of 2.5 to 4.5 mm.
(15) The pharmaceutical preparation as defined in item (1), which is a
sheet gel.
(16) The pharmaceutical preparation as defined in item (1), which is a
spherical preparation and of which a diameter is in the range of 20 to 25
mm.
(17) The pharmaceutical preparation as defined in item (1), which is a
paste gel.
(18) The pharmaceutical preparation as defined in item (1), wherein the
drug is a therapeutic drug for endometriosis.
(19) The pharmaceutical preparation as defined in item (1), wherein the
therapeutic drug is danazol.
(20) Use of a chemically modified hyaluronic acid or a salt thereof as a
carrier for manufacturing the pharmaceutical preparation for the treatment
of gynecological diseases, characterized in that the chemically modified
hyaluronic acid or a salt thereof are prepared by O-acylating,
alkoxylating or crosslinking a complex of hyaluronic acid or a salt
thereof and a cationic compound in a nonaqueous solvent.
BEST MODE FOR
CARRYING OUT THE INVENTION
The term "biodegradable polymer" used
herein means a polymer which is degradable and/or absorbable in a mammal
body including a human body. Examples of the biodegradable polymer include
hyaluronic acid, chondroitin and sulfated polysaccharides such as heparin,
heparan sulfate, chondroitin sulfate and dermatan sulfate and salts
thereof, water soluble polysaccharides such as alginic acid,
polygalacturonic acid, dextran and carboxymethyl chitin and salts thereof,
proteins such as collagen, polyamino acids and salts thereof such as
polyglutamic acid, and hydrophilic polymers such as polyethylene glycol,
polyvinyl alcohols and the like, but not limited thereto. Furthermore, the
aforementioned compounds which have been chemically modified may be
included in the present invention. In this invention, a chemical
modification may include organic synthetic modifications and enzymatic
modifications, but not limited thereto.
When the pharmaceutical preparation for the treatment of endometriosis
according to the present invention is prepared with at least one of the
biodegradable polymer selected from the group consisting of
polysaccharides such as hyaluronic acid, heparin, heparan sulfate,
chondroitin, chondroitin sulfate and dermatan sulfate and salts thereof,
alginic acid and a salt thereof, polygalacturonic acid and a salt thereof,
proteins such as collagen and polyamino acids such as polyglutamic acid
and salts thereof as a carrier, the intrauterine or intravaginal
degradation of the carrier and the release of the therapeutic drug
accompanied thereby are induced by the action of intrinsic hydrolytic
enzymes and thus the improved delivery of drugs to the lesion will be
expected.
Particularly, using hyaluronic acid or a salt thereof or a material
principally comprising hyaluronic acid or a salt thereof as a carrier of
the drug for the intrauterine or intravaginal administration, the
intrauterine or intravaginal degradation of the carrier and the release of
the therapeutic drug accompanied thereby highly correlate with intrinsic
activity of hyaluronidase of a patient, and thus the improved delivery of
drugs will be offered. Therefore, hyaluronic acid or a salt thereof is
preferably employed in the present invention.
when hyaluronic acid or a salt thereof is employed as a carrier, it is not
clearly confirmed that the rate or velocity of intrauterine or
intravaginal degradation of the carrier and the release of the therapeutic
drug accompanied thereby. However, the existence of a hyalutonate
degrading enzyme such as hyaluronidase has been determined and an active
oxygen in the uterus and the vagina has also been detected. These
activities of degradation are changeable to the menstrual cycle and thus
these changes are available for the effective release of the therapeutic
drug.
A duration of the sustained release or the drug efficacy of the
pharmaceutical preparation for the treatment of gynecological diseases
according to the invention can be decided dependent on a patient's
condition, a therapeutic purpose thereof or the like. The duration of the
sustained release can be controlled by using a degradation rate of a
biodegradable polymer employed in the invention and a surface area and
volume of the pharmaceutical preparation. The degradation rate of a
biodegradable polymer can be controlled by using properties of the
biodegradable polymer such as species, structure and degree of the
chemical modification, three dimensional structure, an average molecular
weight or the like.
For instance, where a biodegradable polymer is the aforementioned
chemically modified hyaluronic acid or a salt thereof, the resistance to
the degradation by a hyalutonate degrading enzyme and an active oxygen can
be provided to decrease the degradation rate or to prolong the duration of
the sustained release. In this case, it is preferable to increase the
degree of the intramolecular and intermolecular crosslinking of the
chemically modified hyaluronic acid or a salt thereof by using a
crosslinking agent.
If a drug to be supported is a hydrophobic compound such as danazol, it is
possible to decrease the degradation rate or to prolong the duration of
the sustained release using as a carrier a chemically modified hyaluronic
acid or a salt thereof prepared by O-acylating, alkoxylating or
crosslinking a complex of hyaluronic acid or a salt thereof and a cationic
compound in a nonaqueous solvent.
Hyaluronic acid or a salt thereof employed in this invention may be
derived from, but not limited to, various animal tissues such as a tissue
of comb or microorganisms which are capable of producing hyaluronic acid.
Hyaluronic acid or a salt thereof is preferably derived from the
microorganisms. Examples of the microorganisms capable of producing
hyaluronic acid may include Streptococcus pyogenes, Streptococcus
equisimilis, Streptococcus equi, Streptococcus dysgalactiae, Streptococcus
zooepidemicus and the like.
An average molecular weight of the hyaluronates used in the present
invention as a raw material, which is measured by the viscometry, is at
least 10,000, preferably more than 100,000, more preferably in the range
of 500,000 to 1,500,000.
Examples of the cationic compound used in the present invention may
include quaternary ammonium salts, amino acids having two or more amino
groups, peptides, salts of polyamino acids, salts of sugars having two or
more amino groups, preferably quaternary ammonium salts.
Examples of the quaternary ammonium salts include
distearyldimethylammonium chloride, dioleyldimethylammonium chloride,
cetylpyridinium chloride, cetyltrimethylammonium chloride,
cetyltrimethylammonium bromide, ditetradecyldimethylammonium bromide,
didodecyldimethylammonium bromide, didecyldimethylammonium bromide,
octadecyltrimethylammonium chloride, n-octadecyltrimethylammonium bromide,
tridodecylmethylammonium chloride, trioctylmethylammonium bromide,
dioctanoyl L-α-phosphatidylcholine, dilauroyl L-α-phosphatidylcholine,
phosphatidylcholine, dipalmitoyl D,L-α-phosphatidylcholine,
1,2-dimyristoyl-3-trimethylammonium propane,
1,2-dioleoyl-3-trimethylammonium propane,
1,2-dipalmitoyl-3-trimethylammonium-propane,
1,2-distearoyl-3-trimethylammonium propane, benzalkonium chloride,
benzethonium chloride and the like.
In the specification, the complex of hyaluronic acid or a salt thereof and
the cationic compound means a complex in which an anionic moiety such as
the carboxyl group of hyaluronic acid or a salt thereof and the cationic
compound form an ionic-bond. An example of method for preparing the
complex is illustrated below.
<Preparation of a Complex Consisting of the Hyaluronate and the Cationic
Compound>
(A) The hyaluronate is dissolved in
distilled water or purified water corresponding thereto at the
concentration in the range of 0.01% to 10%, preferably 0.05% to 1%. In the
present invention, "purified water corresponding to distilled water" means
water purified, for example, with by the electric deionization and the
reverse osmosis procedures.
(B) The cationic compound to be
complexed with the hyaluronate, preferably the quaternary ammonium salt is
added and dispersed in distilled water or corresponding purified water.
The solution of the hyaluronate prepared in (A) and the solution of the
cationic compound prepared in (B) are mixed so that the molar ratio of the
cationic group in the cationic compound to the carboxyl group in the
hyaluronate is in the range of 0.5-5:1, preferably 0.7-1.5:1, for example
1:1.
The mixing may be performed at room temperature. Preferably, both the
solutions are heated up to the gel-liquid crystal transition point
temperature of the cationic compound and mixed at an temperature equal or
higher than that temperature.
The insoluble product obtained by the mixing can be recovered from the
mixture by a separation method conventionally employed in the art, for
example, centrifugation, suction filtration, pressure filtration or the
like. The insoluble product recovered is washed with water or purified
water corresponding thereto which has been heated up to the gel-liquid
crystal transition point temperature or higher and then subjected to
drying. The drying can be carried out by means of any drying procedure
conventionally employed in the art, e.g. atmospheric drying, vacuum
drying, freeze drying or the like.
Examples of the nonaqueous solvents include chloroform, methylene
chloride, toluene, heptane, ethanol, methanol, propylene glycol, ethylene
glycol, dimethylformamide (DMF), dimethyl sulfoxide (DMSO),
tetrahydrofuran (THF) and a mixed solvent thereof. The concentration of
the complex consisting of the hyaluronate and the cationic compound is
preferably in the range of 1 to 1000 mmol/L, but not limited thereto.
Examples of the O-acylation in the present invention may include (1) a
reaction with an organic acid employing one or more acid catalysts, for
example, mineral acids such as hydrochloric acid or sulfuric acid, organic
acids such as aromatic sulfonic acid and Lewis acids such as boron
fluoride etherate or the like, (2) a reaction with an organic acid
employing one or more dehydrating agents, for example, N,N′-dicyclohexylcarbodiimide,
2-chloro-1-methyl pyridiniumiodide and N,N′-carbonyl diimidazole or the
like, and (3) an O-acylation employing an acid anhydride or an acid
halide, e.g. the Schotten-Baumann method in the presence of an acid
binder, such as sodium acetate, triethylamine, pyridine, 4-dimethylamino
pyridine or the like.
Examples of the alkoxylation in the invention may include (1) a reaction
using an alkyl halide and an alkoxide, e.g. the Williamson reaction and
(2) a dehydration of hydroxyl groups using Brönsted acid or Lewis acid as
an acid catalyst.
Examples of the crosslinking reaction may include a photocrosslinking
reaction by the irradiation such as gamma-ray irradiation, an auto-crosslinking
reaction by adjusting pH of a solution containing hyaluronic acid or a
salt thereof and optionally by repeating freeze-thaw, and a crosslinking
reaction using as a crosslinking agent (1) polyfunctional aldehydes such
as glutaraldehyde and terephthalaldehyde, (2) polyfunctional epoxy
compounds such as epichlorohydrin, 1,2-bis(2,3-epoxypropoxy)ethane,
ethyleneglycol diglycidyl ether or (3) polyhydric alcohols such as
ethylene glycol and propylene glycol.
According to the present invention,a weight ratio of a therapeutic drug
for the intrauterine, intravaginal or intrapelvic administration, or for
the administration into the ovarian endometrioma to a biodegradable
polymer (i.e. [Drug]/[Polymer]) is preferably in the range of 1/1000 to
10/1, more preferably in the range of 1/10 to 2/1. Within the range of the
weight ratio, the therapeutic drug for the intrauterine, intravaginal or
intrapelvic administration, or for the administration into the ovarian
endometrioma can be effectively released from the pharmaceutical
preparation according to the invention. When a double-layer preparation is
manufacturing as mentioned below, the outer layer of the preparation is
preferably in the aforementioned range of the weight ratio of the drug to
the polymer.
The pharmaceutical preparation for the treatment of gynecological diseases
according to the present invention can be manufactured by a process which
comprises mixing a therapeutic drug for the intrauterine, intravaginal or
intrapelvic administration, or for the administration into the ovarian
endometrioma and a biodegradable polymer in powder form, dissolving or
suspending the mixture in a solvent into which the polymer is soluble,
pouring into a mold and removing the solvent.
In addition to the therapeutic drug for the treatment of gynecological
diseases, the pharmaceutical preparation according to the present
invention may include sugars, amino acids, peptides, proteins, enzymes,
lipids, minerals, organic salts, metals or the like without the reduction
in an effect of drugs.
When the preparation according to the present invention is directed to a
preparation for inserting into the uterine cavity, the vagina, the pelvis
or the ovarian endometrioma, the preparation has any form, shape and size
suitable for the desired administration and is not particularly limited.
The form thereof may be a solid, gel or liquid form. For the intrauterine
administration, the shape thereof may be T-shaped form, intra uterine
device-like ring (hereinafter referred to as "IUD-like ring"), sheet gel
or the ring or paste gel. For the intrapelvic administration or the
administration into the ovarian endometrioma, the shape may be a sheet gel
or paste gel.
The size of the preparation according to the present invention may be
varied dependent on a purpose of use or the subject to be administered.
When a subject is human and the preparation of the invention is a T-shaped
preparation, a length of a vertical bar of the preparation is in the range
of 20 to 40 mm, preferably 30 to 35 mm and a length of a transverse is in
the range of 25 to 45 mm, preferably 30 to 38 mm. A diameter of the
vertical bar is in the range of 1.0 to 3.0 mm and a diameter of the
transverse bar is in the range of 3.0 to 4.0 mm, preferably 3.2 to 3.6 mm.
When the preparation is a IUD-like ring, an outside diameter thereof is in
the range of 20 to 25 mm and a thickness is in the range of 2.5 to 4.5 mm,
preferably 3.0 mm.
When the preparation is a sheet gel preparation, a width thereof is in the
range of 10 to 50 mm, preferably 20 to 30 mm, a length is in the range of
20 to 70 mm, preferably 40 to 60 mm and a thickness is in the range of 2
to 20 mm, preferably 5 to 10 mm.
When the preparation is a spherical gel preparation, a diameter thereof is
in the range of 10 to 30 mm, preferably 20 to 25 mm. When the preparation
is a ring preparation for the intravaginal administration, an outer
diameter thereof is in the range of 30 to 60 mm, preferably 45 to 55 mm
and a thickness of the ring is in the range of 4.0 to 12.0 mm, preferably
7.5 to 10.0 mm. In the case of a paste gel preparation, a size thereof is
not particularly limited.
When the preparation according to the present invention is the T-shaped
preparation or the IUD-like ring, the preparation may be composed of a
monolayer or a double layer which includes a core of plastic or the like
in order to increase the strength of the preparation.
When a core is used for manufacturing the T-shaped preparation for the
intrauterine administration, the core is usually included in both the
vertical and transverse bars. A length of the core is in the range of 55
to 70% of each bar and a diameter of the core is in the range of 60 to 90%
of each bar. Further, the drug is deposited on the vertical bar. The
T-shaped preparation for the intrauterine administration may be preferably
attached a nylon monofilament at lower end of the vertical bar thereof. A
length of the nylon monofilament is in the range of 30 to 400 mm,
preferably 50 to 280 mm and a diameter thereof is in the range of 0.170 to
0.290 mm.
The ring preparation according to the present invention may be constructed
as a monolayer or double layer ring in order to improve the release
efficiency of the drug dependent on the desired duration of the treatment
and the degree of symptoms to be treated. In the case of the double layer
ring preparation for the intravaginal administration, a thickness of the
outer layer is at least 0.1 mm, preferably in the range of 0.1 to 2.0 mm.
The pharmaceutical preparations for the treatment of gynecological
diseases according to the present invention can be manufactured by
conventional techniques employed for the manufacturing the preparations
for the intrauterine, intravaginal or intrapelvic administration, or for
the administration into the ovarian endometrioma. For instance, the
monolayer preparation can be manufactured by a process which comprises
transferring danazol and a base material of a carrier into a vessel placed
in a clean bench, adding a crosslinking agent thereto, mixing the mixture
for 20 to 30 minutes at room temperature, pouring the mixture into a mold
and then hardening at room temperature. The amounts and weight ratio of
danazol and a base material of the carrier are set within the
aforementioned ranges. A mold suitable for the aforementioned shape and
size of the preparation is also employed.
The double layer preparation can be manufactured in the same manner of the
aforementioned manufacture of the monolayer preparation, except for
embedding a desired core into the mold at the step for molding the
obtained mixture. The aforementioned cores can be employed.
The preparations according to the present invention are required aseptic.
Therefore, all steps of the manufacture are carried out under the sterile
condition and the final preparations are packaged with a packaging
material such as aluminum heat seal or the like.
According to the present invention, examples of a therapeutic drug for the
intrauterine, intravaginal or intrapelvic administration, or for the
administration into the ovarian endometrioma may include therapeutic drugs
for endometriosis, contraceptives, antipyretics, hormone drugs,
antihormone drugs, therapeutic drugs for endometrioid carcinoma,
inhibitors of hormone synthesis, antibiotics, antifungal drugs,
therapeutic drugs for vaginosis, therapeutic drugs for trichomoniasis,
therapeutic drugs for cervical uterocervical cancer and the like, but not
limited thereto. Preferable is a therapeutic drug for endometriosis
because of the improved drug delivery to the local lesion according to the
invention.
Examples of the therapeutic drug for endometriosis include danazol,
nonsteroidal antipyretic and analgesic drugs, herbal drugs, progestogen,
estrogen, GnRH-antagonists, gestrinone, antiestorogens, aromatase
inhibitors and the like. Most preferable is danazol because a considerable
drug efficiency can be expected when the drug is locally administered.
When the preparation according to the present invention contains danazol
as a therapeutic drug for endometriosis, a preferable carrier may include
hyaluronic acid, a salt thereof e.g. ammonium hyaluronate or sodium
hyaluronate which have been chemically modified or not. These carriers can
satisfactorily support danazol within a gel thereof and momentarily
release the drug due to their superior responsibility to hyaluronidase or
an active oxygen.
The preparation according to the present invention which comprises the
therapeutic drug for endometriosis is applicable for both the internal
endometriosis and the external endometriosis.
The subject to be administered the preparation according to the invention
is not limited to human and may include female of mammal such as swine,
cattle, horse, sheep, dog, cat, monkey or the like.
Claim 1 of 12 Claims
1. A pharmaceutical
preparation for the treatment of gynecological diseases which comprises a
therapeutic drug for the intrauterine, intravaginal or intrapelvic
administration, or for the administration into the ovarian endometrioma and
a biodegradable polymer comprising chemically modified hyaluronic acid or a
salt thereof, wherein the chemically modified hyaluronic acid or a salt
thereof is prepared by O-acylating a complex of hyaluronic acid or a salt
thereof and a quaternary ammonium salt in a non-aqueous solvent and contains
a decreased amount of a pyrogen and/or an antigenic substance, said amount
has been decreased by the O-acylating in the non-aqueous solvent to the
extent that the amount of the pyrogen is not more than 0.05 endotoxin unit (EU)/mg,
and wherein the drug is supported by the biodegradable polymer as a carrier.
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