U.S. patent application number 11/782707 was filed with the patent office on 2008-01-17 for sustained release compositions, process for producing the same and use thereof.
This patent application is currently assigned to Takeda Pharmaceutical Company Limited. Invention is credited to Yoshio Hata, Yasutaka Igari, Kazumichi Yamamoto.
Application Number | 20080014237 11/782707 |
Document ID | / |
Family ID | 16448493 |
Filed Date | 2008-01-17 |
United States Patent
Application |
20080014237 |
Kind Code |
A1 |
Igari; Yasutaka ; et
al. |
January 17, 2008 |
SUSTAINED RELEASE COMPOSITIONS, PROCESS FOR PRODUCING THE SAME AND
USE THEREOF
Abstract
Sustained release compositions containing a physiologically
active substance or its salt, hydroxynaphthoic acid or its salt and
a lactic acid-glycolic polymer or its salt, wherein the product of
the weight-average molecular weight of the lactic acid-glycolic
acid polymer by the amount (.mu.mol) of the terminal carboxyl group
per unit mass (g) of the lactic acid-glycolic acid polymer is from
1,200,000 to 3,000,000 (inclusive); and their production;
medicaments containing these sustained release compositions,
etc.
Inventors: |
Igari; Yasutaka; (Kobe,
JP) ; Hata; Yoshio; (Hokkaido, JP) ; Yamamoto;
Kazumichi; (Kyoto-shi, JP) |
Correspondence
Address: |
FOLEY AND LARDNER LLP;SUITE 500
3000 K STREET NW
WASHINGTON
DC
20007
US
|
Assignee: |
Takeda Pharmaceutical Company
Limited
|
Family ID: |
16448493 |
Appl. No.: |
11/782707 |
Filed: |
July 25, 2007 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10019786 |
Jan 4, 2002 |
7265157 |
|
|
PCT/JP00/04683 |
Jul 13, 2000 |
|
|
|
11782707 |
Jul 25, 2007 |
|
|
|
Current U.S.
Class: |
424/422 ;
424/486; 514/10.3; 514/19.5; 514/784 |
Current CPC
Class: |
A61P 15/00 20180101;
A61P 35/00 20180101; A61P 13/08 20180101; A61P 5/24 20180101; A61K
9/1647 20130101; A61K 9/0024 20130101; A61K 9/1617 20130101 |
Class at
Publication: |
424/422 ;
424/486; 514/015; 514/002; 514/784 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 38/02 20060101 A61K038/02; A61K 38/09 20060101
A61K038/09; A61K 47/12 20060101 A61K047/12 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 15, 1999 |
JP |
201887/1999 |
Claims
1. A sustained release composition comprising a pharmacologically
active substance or its salt, a hydroxynaphthoic acid or its salt
and a lactic acid-glycolic acid polymer or its salt, wherein the
product of the weight average molecular weight of said lactic
acid-glycolic acid polymer by the amount (.mu.mol) of the terminal
carboxyl group per unit mass (g) of said lactic acid-glycolic acid
polymer is 1,200,000 to 3,000,000 (inclusive).
2. The sustained release composition according to claim 1, wherein
the pharmacologically active substance is a physiologically active
peptide.
3. The sustained release composition according to claim 1, wherein
the pharmacologically active substance is an LH-RH derivative.
4. The sustained release composition according to claim 1, wherein
the hydroxynaphthoic acid is 1-hydroxy-2-naphthoic acid.
5. The sustained release composition according to claim 1, wherein
the % molar ratio between lactic acid and glycolic acid is 100/0 to
40/60.
6. The sustained release composition according to claim 1, wherein
the % molar ratio between lactic acid and glycolic acid is
100/0.
7. The sustained release composition according to claim 1, wherein
the weight average molecular weight of the polymer is about 3,000
to about 100,000.
8. The sustained release composition according to claim 7, wherein
the weight average molecular weight is about 20,000 to about
50,000.
9. The sustained release composition according to claim 3, wherein
the LH-RH derivative is a peptide represented by Formula:
5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z wherein Y denotes DLeu,
DAla, DTrp, DSer(tBu), D2NaI or DHis(ImBzl), and Z denotes
NH--C.sub.2H.sub.5 or Gly-NH.sub.2.
10. The sustained release composition according to claim 1, wherein
the amount (.mu.mol) of the terminal carboxyl group of the polymer
is 50 to 90 .mu.mol per unit mass (g) of the polymer.
11. The sustained release composition according to claim 3, wherein
the molar ratio between the hydroxynaphthoic acid or its salt and
the LH-RH derivative or its salt is 3:4 to 4:3.
12. The sustained release composition according to claim 3 which
contains the LH-RH derivative or its salt in an amount of 12% by
weight to 24% by weight based on the sustained release
composition.
13. The sustained release composition according to claim 1, wherein
the physiologically active substance or its salt is a slightly
water-soluble or water-soluble substance.
14. The sustained release composition according to claim 1 which is
a formulation for injection.
15. A medicament comprising a sustained release composition
according to claim 1.
16. A prophylactic or therapeutic agent against prostate cancer,
prostate hyperplasia, endometriosis, hysteromyoma, metrofibroma,
precocious puberty, dysmenorrhea or mammary cancer or an
contraceptive containing a sustained release composition according
to claim 3.
17. The sustained release composition according to claim 1, wherein
the pharmacologically active substance or its salt is released over
a period of at least 6 months or longer.
18. A sustained release composition comprising a pharmacologically
active substance or its salt, 1-hydroxy-2-naphthoic acid or its
salt and a biodegradable polymer or its salt.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Divisional of application Ser. No.
10/019,786, filed Jan. 4, 2002, which is a National Stage
application of PCT/JP00/04683, filed Jul. 13, 2000, which claims
priority from Japanese patent application JP 201887/1999, filed
Jul. 15, 1999.
FIELD OF THE INVENTION
[0002] The present invention relates to a sustained release
formulation of a pharmacologically active substance and a method
for producing the same.
BACKGROUND OF THE INVENTION
[0003] JP-A-7-97334 discloses a sustained release formulation
consisting of a physiologically active peptide or its salt and a
biodegradable polymer having a terminal free carboxyl group as well
as a method for producing the same.
[0004] Each of GB2209937, GB2234169, GB2234896, GB2257909 and
EP626170A2 discloses a composition comprising as a base a
biodegradable polymer containing a water-insoluble salt such as a
pamoate of a peptide or a protein prepared separately as well as a
method for producing the same.
[0005] WO95/15767 discloses an embonate (pamoate) of cetrorelix
(LH-RH antagonist) and a method for producing the same, and
describes that this pamoate, even when enclosed in a biodegradable
polymer, exhibits the peptide-releasing performance equivalent to
the pamoate which exists independently.
DISCLOSURE OF THE INVENTION
[0006] There is provided a novel composition containing a
physiologically active substance at a high concentration whose
excessive initial release is suppressed whereby accomplishing a
stable releasing rate over a prolonged period (preferably about 6
months or longer).
[0007] The present inventors made an effort to solve the problems
described above and finally discovered that by allowing a
physiologically active substance and a hydroxynaphthoic acid to
coexist upon forming a composition the physiologically active
substance can be introduced at a high concentration into the
composition; that further by enclosing these two components into a
lactic acid-glycolic acid polymer the physiologically active
substance can be released at a releasing rate different from the
rate at which the physiologically active substance is released from
a composition formed from the physiologically active substance and
the hydroxynaphthoic acid prepared in the absence of the lactic
acid-glycolic acid polymer; that this releasing rate can be
controlled by selecting the characteristics of the lactic
acid-glycolc acid polymer and the amount of the hydroxynaphthoic
acid; that an initial excessive release can surely be suppressed
even at a high concentration whereby accomplishing a sustained
release over an extremely prolonged period (preferably about 6
months or longer); and also that by employing a lactic
acid-glycolic acid polymer whose weight average molecular weight
multiplied by the amount (.mu.mol) of the terminal carboxyl group
per unit mass (g) of the lactic acid-glycolic acid polymer is
1,200,000 to 3,000,000 (inclusive) a further satisfactory sustained
release formulation can be provided. As a result of a further
effort, the present invention was completed.
[0008] Thus, the present invention provides:
[0009] (1) a sustained release composition comprising a
pharmacologically active substance or its salt, a hydroxynaphthoic
acid or its salt and a lactic acid-glycolic acid polymer or its
salt, wherein the product of the weight average molecular weight of
said lactic acid-glycolic acid polymer by the amount (.mu.mol) of
the terminal carboxyl group per unit mass (g) of said lactic
acid-glycolic acid polymer is 1,200,000 to 3,000,000
(inclusive);
(2) the sustained release composition according to the
above-mentioned (1), wherein the pharmacologically active substance
is a physiologically active peptide;
(3) the sustained release composition according to the
above-mentioned (1), wherein the pharmacologically active substance
is an LH-RH derivative;
(4) the sustained release composition according to the
above-mentioned (1), wherein the hydroxynaphthoic acid is
1-hydroxy-2-naphthoic acid or 3-hydroxy-2-naphthoic acid;
(5) the sustained release composition according to the
above-mentioned (1), wherein the hydroxynaphthoic acid is
1-hydroxy-2-naphthoic acid.
(6) the sustained release composition according to the
above-mentioned (1) wherein the % molar ratio between lactic acid
and glycolic acid is 100/0 to 40/60;
(7) the sustained release composition according to the
above-mentioned (1), wherein the % molar ratio between lactic acid
and glycolic acid is 100/0;
(8) the sustained release composition according to the
above-mentioned (1), wherein the weight average molecular weight of
the polymer is about 3,000 to about 100,000;
(9) the sustained release composition according to the
above-mentioned
(8), wherein the weight average molecular weight is about 20,000 to
about 50,000;
(10) the sustained release composition according to the
above-mentioned (3), wherein the LH-RH derivative is a peptide
represented by Formula: 5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z
wherein Y denotes DLeu, DAla, DTrp, DSer(tBu), D2Nal or
DHis(ImBzl), and Z denotes NH--C.sub.2H.sub.5 or Gly-NH.sub.2; (11)
the sustained release composition according to the above-mentioned
(1), wherein the amount (.mu.mol) of the terminal carboxyl group of
the polymer is 50 to 90 .mu.mol per unit mass (g) of the polymer;
(12) the sustained release composition according to the
above-mentioned (3), wherein the molar ratio between the
hydroxynaphthoic acid or its salt and the LH-RH derivative or its
salt is 3:4 to 4:3; (13) the sustained release composition
according to the above-mentioned (3) which contains the LH-RH
derivative or its salt in an amount of 12% by weight to 24% by
weight based on the sustained release composition; (14) the
sustained release composition according to the above-mentioned (1),
wherein the physiologically active substance or its salt is a
slightly water-soluble or water-soluble substance; (15) the
sustained release composition according to the above-mentioned (1)
which is a formulation for injection; (16) a method for producing a
sustained release composition according to the above-mentioned (1)
which comprises removing a solvent from a mixture of a
pharmacologically active substance or its salt, a lactic
acid-glycolic acid polymer or its salt and a hydroxynaphthoic acid
or its salt; (17) the method according to the above-mentioned (16)
which comprises mixing the pharmacologically active substance or
its salt with a solution of the lactic acid-glycolic acid polymer
or its salt and the hydroxynaphthoic acid or its salt in an organic
solvent, dispersing the mixture, and then removing the organic
solvent; (18) the method according to the above-mentioned (16),
wherein the pharmacologically active substance or its salt is an
aqueous solution containing the pharmacologically active substance
or its salt; (19) the method according to the above-mentioned (16),
wherein the salt of the pharmacologically active substance is a
salt with a free base or acid; (20) a medicament comprising a
sustained release composition according to the above-mentioned (1);
(21) a prophylactic or therapeutic agent against prostate cancer,
prostate hyperplasia, endometriosis, hysteromyoma, metrofibroma,
precocious puberty, dysmenorrhea or mammary cancer or an
contraceptive containing a sustained release composition according
to the above-mentioned (3); (22) the sustained release composition
according to the above-mentioned (1), wherein the pharmacologically
active substance or its salt is released over a period of at least
6 months or longer; and (23) a sustained release composition
comprising a pharmacologically active substance or its salt,
1-hydroxy-2-naphthoic acid or its salt and a biodegradable polymer
or its salt.
[0010] Furthermore, the invention provides:
[0011] (24) a method for producing a sustained release composition
according to the above-mentioned (16) which comprises producing a
w/o emulsion having as an inner aqueous phase a liquid containing
the physiologically active substance or its salt and as an oil
phase a solution containing the lactic acid-glycolic acid or its
salt and the hydroxynaphthoic acid or its salt followed by removing
a solvent;
[0012] (25) a method for producing a sustained release composition
according to the above-mentioned (16) which comprises producing a
w/o emulsion having as an inner aqueous phase a liquid containing
the hydroxynaphthoic acid or its salt and as an oil phase a
solution containing the physiologically active substance or its
salt and the lactic acid-glycolic acid or its salt followed by
removing a solvent;
[0013] (26) a method for producing a sustained release composition
according to the above-mentioned (16) which comprises mixing the
pharmacologically active substance or its salt with the
hydroxynaphthoic acid or its salt, dissolving the mixture, and then
removing the organic solvent; and
(27) a method for producing a sustained release composition
according to any of the above-mentioned (24) to (26) wherein the
process for removing the solvent is a in-water drying method.
[0014] While a physiologically active substance employed in the
present invention is not limited particularly as long as it is
pharmaceutically useful, it may be a non-peptide compound or a
peptide compound. A non-peptide compound may for example be an
agonist, an antagonist and a compound having an inhibitory effect
on an enzyme. An example of a preferred peptide compound is a
physiologically active peptide having a molecular weight of about
300 to about 40,000, preferably about 400 to about 30,000, more
preferably about 500 to about 20,000.
[0015] Such physiologically active peptide may for example be
luteinization hormone-releasing hormone (LH-RH), insulin,
somatostatin, growth hormone, growth hormone-releasing hormone
(GH-RH), prolactin, erythropoietin, adrenocortical hormone,
melanocyte-stimulating hormone, thyroid hormone-releasing hormone,
thyroid-stimulating hormone, luteinization hormone,
follicle-stimulating hormone, vasopressin, oxytocin, calcitonin,
gastrin, serectin, pancreozymin, cholecystokinin, angiotensin,
human placental lactogen, human chorionic gonadotropin, enkephalin,
endorphin, L-tyrosil, L-arginine, "KYOTORPHIN", tuftsin,
thymopoietin, thymosin, "THYMOTHYMRIN", thymic humoral factor,
blood thymic factor, tumor necrosis factor, colony-inducing factor,
motilin, "DEINORPHINE", bombesin, neurotensin, cerulein,
bradykinin, atrial natriuretic factor, nerve growth factor, cell
growth factor, neurotrophic factor, endothelin-antagonizing peptide
and their derivatives as well as their fragments and derivative
thereof.
[0016] In the present invention, a physiologically active substance
may be employed as it is or as a pharmaceutically acceptable salt
thereof.
[0017] A salt of a physiologically active substance having a basic
group such as an amino group may for example be a salt with an
inorganic acid (referred to also as an inorganic free acid) (e.g.,
carbonic acid, bicarbonic acid, hydrochloric acid, sulfuric acid,
nitric acid, boric acid and the like) and with an organic acid
(referred to also as an organic free acid) (e.g., succinic acid,
acetic acid, propionic acid, trofluoroacetic acid and the
like).
[0018] A salt of a physiologically active substance having an
acidic group such as a carboxyl group may for example be a salt
with an inorganic base (referred to also as an inorganic free base)
(e.g., an alkaline metal such as sodium and potassium, an alkaline
earth metal such as calcium and magnesium) or with an organic base
(referred to also as an inorganic free base) (e.g., an organic
amine such as triethylamine, a basic amino acid such as arginine).
A physiologically active peptide may form a metal complex compound
(e.g., copper complex, zinc complex and the like.
[0019] A preferred example of such physiologically active peptide
is an LH-RH derivative or its salt which is useful for treating a
hormone-dependent disease, especially a sex hormone-dependent
cancer (e.g., prostate cancer, uterine cancer, mammary cancer,
pituitary cancer and the like), a sex hormone-dependent disease
such as prostate hyperplasia, endometriosis, hysteromyoma,
precocious puberty, dysmenorrhea, amenorrhea, premenstrual
syndrome, multilocular ovarian syndrome and the like, and useful as
a contraceptive (or against infertility when utilizing a rebound
effect after discontinuation). Also exemplified is an LH-RH
derivative or its salt which is useful for treating a benign or
malignant tumor which is not sex hormone-dependent but is LH-RH
sensitive.
[0020] Typically, an LH-RH derivative or its salt may for example
be the peptides described in Treatment with GnRH analogs:
Controvesies and perspectives, The Parthenon Publishing Group Ltd.,
(1996), JP-W-3-503165, JP-A-3-101695, 7-97334 and 8-259460.
[0021] An LH-RH derivative may for example be an LH-RH agonist or
an LH-RH antagonist, the latter may for example be a
pharmacologically active peptide represented by Formula [I]:
X-D2Nal-D4ClPhe-D3Pal-Ser-A-B-Leu-C-Pro-DAlaNH.sub.2 Wherein X
denotes N(4H2-furoyl)Gly or NAc, A denotes a residue selected from
NMeTyr, Tyr, Aph(Atz) and NMeAph(Atz), B denotes a residue selected
from DLys(Nic), DCit, DLys(AzaglyNic), DLys(AzaglyFur),
DhArg(Et.sub.2), DAph(Atz) and DhCi, and C denotes Lys(Nisp), Arg
or hArg(Et.sub.2) or its salt.
[0022] An LH-RH agonist may for example be a pharmacologically
active peptide represented by Formula [II]:
5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z wherein Y denotes a
residue selected from DLeu, DAla, DTrp, DSer(tBu), D2NaI and
DHis(ImBzl), and Z denotes NH--C.sub.2H.sub.5 or Gly-NH.sub.2 or
its salt. One preferred especially is a peptide wherein Y is DLeu,
Z is NH--C.sub.2H.sub.5 (i.e., a peptide represented by
5-oxo-Pro-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH--C.sub.2H.sub.5).
[0023] Any of these peptides can be produced by a method described
in the foregoing references and specifications as well as a method
in accordance therewith.
[0024] Abbreviations employed herein are listed below.
TABLE-US-00001 Abbreviation Name N(4H2-furoyl)Gly:
N-tetrahydrofuroyl glycine residue NAc: N-acetyl group D2Nal:
D-3-(2-naphthyl)alanine residue D4ClPhe:
D-3-(4-chloro)phenylalanine residue D3Pal: D-3-(3-pyridyl)alanine
residue NMeTyr: N-methyltyrosine residue Aph(Atz):
N-[5'-(3'-amino-1'H-1',2',4'-triazolyl)]- phenylalanine residue
NmeAph(Atz): N-methyl-[5'-(3'-amino-1'H-1',2',4'-
triazolyl)]phenylalanine residue DLys(Nic):
D-(e-N-nicotinoyl)lysine residue Dcit: D-citrulline residue
DLys(AzaglyNic): D-(azaglycylnicotinoyl)lysine residue
DLys(AzaglyFur): D-(azaglycylfuranyl)lysine residue
DhArg(Et.sub.2): D-(N,N'-diethyl)homoarginine residue Daph(Atz):
D-N-[5'-(3'-amino-1'H-1',2',4'- triazolyl)]phenylalanine residue
DhCi: D-homocitrulline residue Lys(Nisp): (e-N-isopropyl)lysine
residue hArg(Et.sub.2): (N,N'-diethyl)homoarginine residue
DSer(tBu): O-tert-butyl-D-serine Dhis(ImBzl):
N.sup.im-benzyl-D-histidine
[0025] Otherwise, an amino acid, when designated as an
abbreviation, is represented as found in IUPAC-IUB Commission on
Biochemical Nomenclature, European Journal of Biochemistry, Vol.
138, page 9 to 37 (1984) or as customary in the art, and an amino
acid, even when optical isomers thereof exist, means an L form
unless otherwise specified.
[0026] A hydroxynaphthoic acid employed in the invention is a
naphthalene to which one hydroxyl group and one carboxyl group were
bound on different carbon atoms. Accordingly, there were 14 isomers
in total which differ from each other in the position of the
hydroxyl group in relation to each of the 1-position and the
2-position at which the carboxyl group is bound to the naphthalene
ring. The invention may employ any of these isomers as well as a
mixture thereof at any ratio. As described below, one having a
higher acid dissociation constant is preferable, or one having a
lower pKa (pKa=-log 10 Ka wherein Ka is an acid dissociation
constant is preferable. A slightly water-soluble isomer is
preferable.
[0027] One also preferred is an isomer which is soluble in an
alcohol (for example, ethanol and methanol). The expression
"soluble in an alcohol" means that the solubility, for example in
methanol, is 10 g/L or higher.
[0028] While the pKa of 3-hydroxy-2-naphthoic acid (pKa=2.708,
KAGAKUBINRAN, II, NIPPON KAGAKUKAI, Published on Sep. 25, 1969) is
the only known pKa among hydroxynaphthoic acid isomers, a
comparison of the pKa between the three isomers of hydroxybenzoic
acid serves to give a useful information. Thus, the pKas of
m-hydroxybenzoic acid and p-hydroxybenzoic acid are 4 or higher,
while the pKa of o-hydroxybenzoic acid (salicylic acid) is far
lower (=2.754). Accordingly, 3-hydroxy-2-naphthoic acid,
1-hydroxy-2-naphthoic acid and 2-hydroxy-1-naphthoic acid each
having a carboxyl group and a hydroxyl group bound to the adjacent
carbon atoms in the naphthalene ring are preferred among the 14
isomers described above.
[0029] A hydroxynaphthoic acid may be a salt. Such salt may for
example be a salt with an inorganic base (e.g., an alkaline metal
such as sodium and potassium, an alkaline earth metal such as
calcium and magnesium), with an organic base (e.g., an organic
amine such as triethylamine, a basic amino acid such as arginine),
or with a transition metal (e.g., zinc, iron, copper) as well as a
complex salt.
[0030] An example of a method for producing a hydroxynaphthoate of
a pharmaceutically active substance of the invention is described
below.
[0031] (1) A solution of a hydroxynaphthoic acid in a hydrated
organic solvent is loaded onto and adsorbed by a weakly basic ion
exchange column until saturation. Subsequently, the hydrated
organic solvent is loaded to remove excessive hydroxynaphthoic acid
and then a solution of a physiologically active substance or its
salt in a hydrated organic solvent is loaded to effect an ion
exchange, and the resultant effluent is made free of the solvent.
Such hydrated organic solvent contains as an organic solvent an
alcohol (e.g., methanol, ethanol), acetonitrile, tetrahydrofuran,
dimethylformamide and the like. A method for removing the solvent
to precipitate a salt may be a method known per se or a method in
accordance therewith. For example, the solvent is evaporated off
with adjusting the vacuum level using a rotary evaporator.
[0032] (2) The exchange ion of a strongly basic ion exchange column
has previously been replaced with a hydroxide ion and then is
loaded with a solution of a physiologically active substance or its
salt in a hydrated organic solvent whereby exchanging the basic
groups into the hydroxides. The recovered effluent was used to
dissolve a hydroxynaphthoic acid in an amount less than the
equivalent, concentrated to precipitate a salt, which is dried if
necessary after washing with water.
[0033] Since a hydroxynaphthoate of a physiologically active
substance is slightly water-soluble although the solubility may
vary depending on the physiologically active substance employed, it
can be used as a sustained release formulation utilizing the
sustained releasing ability of the physiologically active peptide
salt itself or it can further be formulated into a sustained
release composition.
[0034] A lactic acid-glycolic acid polymer employed in the
invention is a lactic acid-glycolic acid polymer whose weight
average molecular weight multiplied by the amount (.mu.mol) of the
terminal carboxyl group per unit mass (g) of the lactic
acid-glycolic acid polymer is 1,200,000 to 3,000,000 (inclusive),
preferably 1,500,000 to 2,600,000 (inclusive), with one having a
terminal free carboxyl group being employed preferably.
[0035] A lactic acid-glycolic acid polymer may be in the form of a
salt. Such salt may for example be a salt with an inorganic base
(e.g., an alkaline metal such as sodium and potassium, an alkaline
earth metal such as calcium and magnesium), with an organic base
(e.g., an organic amine such as triethylamine, a basic amino acid
such as arginine), or with a transition metal (e.g., zinc, iron,
copper) as well as a complex salt.
[0036] Such polymer has a % molar ratio between lactic acid and
glycolic acid ranging preferably from about 100/0 to about 40/60,
more preferably from about 100/0 to about 50/50. A lactic acid
homopolymer whose % molar ratio is 100/0 is also employed
preferably.
[0037] The optical isomer ratio of lactic acid which is one of the
least repeating units of "lactic acid-glycolic acid polymer"
described above, when represented as D-form/L-form (% mol/mol), is
preferably about 75/25 to about 25/75. Those having a ratio of
D-form/L-form (% mol/mol) especially of about 60/40 to about 30/70
are employed frequently.
[0038] The weight average molecular weight of "lactic acid-glycolic
acid polymer" described above is usually about 3,000 to about
100,000, preferably about 3,000 to about 60,000, more preferably
about 3,000 to about 50,000, especially about 20,000 to about
50,000.
[0039] A lactic acid-glycolic acid polymer of the invention may for
example be a polymer having a weight average molecular weight
multiplied by the amount (.mu.mol) of the terminal carboxyl group
per unit mass (g) of the lactic acid-glycolic acid polymer of
1,200,000 to 3,000,000 (inclusive), more preferably a polymer
having a weight average molecular weight multiplied by the amount
(.mu.mol) of the terminal carboxyl group per unit mass (g) of the
lactic acid-glycolic acid polymer of 1,500,000 to 2,600,000
(inclusive).
[0040] The polydispersity (weight average molecular weight/number
average molecular weight) is usually about 1.2 to about 4.0,
preferably about 1.5 to about 3.5, more preferably about 1.7 to
about 3.0.
[0041] The amount of the free carboxyl group of "lactic
acid-glycolic acid polymer" described above per unit mass (g) of
the polymer is usually about 20 to about 1000 .mu.mol, more
preferably about 40 to about 1000 .mu.mol. A further preferable
amount is about 40 to about 95 .mu.mol, especially about 50 to
about 90 .mu.mol.
[0042] Preferred examples are:
[0043] (1) a lactic acid-glycolic acid polymer whose weight average
molecular weight is about 3,000 to about 100,000 and whose weight
average molecular weight multiplied by the amount (.mu.mol) of the
terminal carboxyl group per unit mass (g) of the lactic
acid-glycolic acid polymer is 1,200,000 to 3,000,000
(inclusive);
[0044] (2) a lactic acid-glycolic acid polymer whose weight average
molecular weight is about 3,000 to about 60,000 and whose weight
average molecular weight multiplied by the amount (.mu.mol) of the
terminal carboxyl group per unit mass (g) of the lactic
acid-glycolic acid polymer is 1,200,000 to 3,000,000
(inclusive);
[0045] (3) a lactic acid-glycolic acid polymer whose weight average
molecular weight is about 3,000 to about 50,000 and whose weight
average molecular weight multiplied by the amount (.mu.mol) of the
terminal carboxyl group per unit mass (g) of the lactic
acid-glycolic acid polymer is 1,200,000 to 3,000,000
(inclusive);
[0046] (4) a lactic acid-glycolic acid polymer whose weight average
molecular weight is about 20,000 to about 50,000 and whose weight
average molecular weight multiplied by the amount (.mu.mol) of the
terminal carboxyl group per unit mass (g) of the lactic
acid-glycolic acid polymer is 1,200,000 to 3,000,000
(inclusive);
[0047] (5) a lactic acid-glycolic acid polymer whose amount
(.mu.mol) of the terminal carboxyl group per unit mass (g) of the
lactic acid-glycolic acid polymer is about 20 to about 1000 .mu.mol
and whose weight average molecular weight multiplied by the amount
(.mu.mol) of the terminal carboxyl group per unit mass (g) of the
lactic acid-glycolic acid polymer is 1,200,000 to 3,000,000
(inclusive);
[0048] (6) a lactic acid-glycolic acid polymer whose amount
(.mu.mol) of the terminal carboxyl group per unit mass (g) of the
lactic acid-glycolic acid polymer is about 40 to about 1000 .mu.mol
and whose weight average molecular weight multiplied by the amount
(.mu.mol) of the terminal carboxyl group per unit mass (g) of the
lactic acid-glycolic acid polymer is 1,200,000 to 3,000,000
(inclusive);
[0049] (7) a lactic acid-glycolic acid polymer [1] whose weight
average molecular weight is about 3,000 to about 100,000, [2] whose
amount (.mu.mol) of the terminal carboxyl group per unit mass (g)
of the lactic acid-glycolic acid polymer is about 20 to about 1000
.mu.mol and [3] whose weight average molecular weight multiplied by
the amount (.mu.mol) of the terminal carboxyl group per unit mass
(g) of the lactic acid-glycolic acid polymer is 1,200,000 to
3,000,000 (inclusive);
[0050] (8) a lactic acid-glycolic acid polymer [1] whose weight
average molecular weight is about 3,000 to about 100,000, [2] whose
amount (.mu.mol) of the terminal carboxyl group per unit mass (g)
of the lactic acid-glycolic acid polymer is about 40 to about 1000
.mu.mol and [3] whose weight average molecular weight multiplied by
the amount (.mu.mol) of the terminal carboxyl group per unit mass
(g) of the lactic acid-glycolic acid polymer is 1,200,000 to
3,000,000 (inclusive);
[0051] (9) a lactic acid-glycolic acid polymer [1] whose weight
average molecular weight is about 3,000 to about 60,000, [2] whose
amount (.mu.mol) of the terminal carboxyl group per unit mass (g)
of the lactic acid-glycolic acid polymer is about 20 to about 1000
.mu.mol and [3] whose weight average molecular weight multiplied by
the amount (.mu.mol) of the terminal carboxyl group per unit mass
(g) of the lactic acid-glycolic acid polymer is 1,200,000 to
3,000,000 (inclusive);
[0052] (10) a lactic acid-glycolic acid polymer [1] whose weight
average molecular weight is about 3,000 to about 60,000, [2] whose
amount (.mu.mol) of the terminal carboxyl group per unit mass (g)
of the lactic acid-glycolic acid polymer is about 40 to about 1000
.mu.mol and [3] whose weight average molecular weight multiplied by
the amount (.mu.mol) of the terminal carboxyl group per unit mass
(g) of the lactic acid-glycolic acid polymer is 1,200,000 to
3,000,000 (inclusive);
[0053] (11) a lactic acid-glycolic acid polymer [1] whose weight
average molecular weight is about 3,000 to about 50,000, [2] whose
amount (.mu.mol) of the terminal carboxyl group per unit mass (g)
of the lactic acid-glycolic acid polymer is about 20 to about 1000
.mu.mol and [3] whose weight average molecular weight multiplied by
the amount (.mu.mol) of the terminal carboxyl group per unit mass
(g) of the lactic acid-glycolic acid polymer is 1,200,000 to
3,000,000 (inclusive);
[0054] (12) a lactic acid-glycolic acid polymer [1] whose weight
average molecular weight is about 3,000 to about 50,000, [2] whose
amount (.mu.mol) of the terminal carboxyl group per unit mass (g)
of the lactic acid-glycolic acid polymer is about 40 to about 1000
.mu.mol and [3] whose weight average molecular weight multiplied by
the amount (.mu.mol) of the terminal carboxyl group per unit mass
(g) of the lactic acid-glycolic acid polymer is 1,200,000 to
3,000,000 (inclusive);
[0055] (13) a lactic acid-glycolic acid polymer [1] whose weight
average molecular weight is about 20,000 to about 50,000, [2] whose
amount (.mu.mol) of the terminal carboxyl group per unit mass (g)
of the lactic acid-glycolic acid polymer is about 20 to about 1000
.mu.mol and [3] whose weight average molecular weight multiplied by
the amount (.mu.mol) of the terminal carboxyl group per unit mass
(g) of the lactic acid-glycolic acid polymer is 1,200,000 to
3,000,000 (inclusive); and
[0056] (14) a lactic acid-glycolic acid polymer [1] whose weight
average molecular weight is about 20,000 to about 50,000, [2] whose
amount (.mu.mol) of the terminal carboxyl group per unit mass (g)
of the lactic acid-glycolic acid polymer is about 40 to about 1000
.mu.mol and [3] whose weight average molecular weight multiplied by
the amount (.mu.mol) of the terminal carboxyl group per unit mass
(g) of the lactic acid-glycolic acid polymer is 1,200,000 to
3,000,000 (inclusive).
[0057] More preferred example are:
[0058] (15) a lactic acid-glycolic acid polymer [1] whose weight
average molecular weight is about 3,000 to about 100,000 and [2]
whose weight average molecular weight multiplied by the amount
(.mu.mol) of the terminal carboxyl group per unit mass (g) of the
lactic acid-glycolic acid polymer is 1,500,000 to 2,600,000
(inclusive);
[0059] (16) a lactic acid-glycolic acid polymer [1] whose weight
average molecular weight is about 3,000 to about 60,000 and [2]
whose weight average molecular weight multiplied by the amount
(.mu.mol) of the terminal carboxyl group per unit mass (g) of the
lactic acid-glycolic acid polymer is 1,500,000 to 2,600,000
(inclusive);
[0060] (17) a lactic acid-glycolic acid polymer [1] whose weight
average molecular weight is about 3,000 to about 50,000 and [2]
whose weight average molecular weight multiplied by the amount
(.mu.mol) of the terminal carboxyl group per unit mass (g) of the
lactic acid-glycolic acid polymer is 1,500,000 to 2,600,000
(inclusive);
[0061] (18) a lactic acid-glycolic acid polymer [1] whose weight
average molecular weight is about 20,000 to about 50,000 and [2]
whose weight average molecular weight multiplied by the amount
(.mu.mol) of the terminal carboxyl group per unit mass (g) of the
lactic acid-glycolic acid polymer is 1,500,000 to 2,600,000
(inclusive);
[0062] (19) a lactic acid-glycolic acid polymer [1] whose amount
(.mu.mol) of the terminal carboxyl group per unit mass (g) of the
lactic acid-glycolic acid polymer is about 20 to about 1000 .mu.mol
and [2] whose weight average molecular weight multiplied by the
amount (.mu.mol) of the terminal carboxyl group per unit mass (g)
of the lactic acid-glycolic acid polymer is 1,500,000 to 2,600,000
(inclusive);
[0063] (20) a lactic acid-glycolic acid polymer [1] whose amount
(.mu.mol) of the terminal carboxyl group per unit mass (g) of the
lactic acid-glycolic acid polymer is about 40 to about 1000 .mu.mol
and [2] whose weight average molecular weight multiplied by the
amount (.mu.mol) of the terminal carboxyl group per unit mass (g)
of the lactic acid-glycolic acid polymer is 1,500,000 to 2,600,000
(inclusive);
[0064] (21) a lactic acid-glycolic acid polymer [1] whose weight
average molecular weight is about 3,000 to about 100,000 and [2]
whose amount (.mu.mol) of the terminal carboxyl group per unit mass
(g) of the lactic acid-glycolic acid polymer is about 20 to about
1000 .mu.mol and [3] whose weight average molecular weight
multiplied by the amount (.mu.mol) of the terminal carboxyl group
per unit mass (g) of the lactic acid-glycolic acid polymer is
1,500,000 to 2,600,000 (inclusive);
[0065] (22) a lactic acid-glycolic acid polymer [1] whose weight
average molecular weight is about 3,000 to about 100,000 and [2]
whose amount (.mu.mol) of the terminal carboxyl group per unit mass
(g) of the lactic acid-glycolic acid polymer is about 40 to about
1000 .mu.mol and [3] whose weight average molecular weight
multiplied by the amount (.mu.mol) of the terminal carboxyl group
per unit mass (g) of the lactic acid-glycolic acid polymer is
1,500,000 to 2,600,000 (inclusive);
[0066] (23) a lactic acid-glycolic acid polymer [1] whose weight
average molecular weight is about 3,000 to about 60,000 and [2]
whose amount (.mu.mol) of the terminal carboxyl group per unit mass
(g) of the lactic acid-glycolic acid polymer is about 20 to about
1000 .mu.mol and [3] whose weight average molecular weight
multiplied by the amount (.mu.mol) of the terminal carboxyl group
per unit mass (g) of the lactic acid-glycolic acid polymer is
1,500,000 to 2,600,000 (inclusive);
[0067] (24) a lactic acid-glycolic acid polymer [1] whose weight
average molecular weight is about 3,000 to about 60,000 and [2]
whose amount (.mu.mol) of the terminal carboxyl group per unit mass
(g) of the lactic acid-glycolic acid polymer is about 40 to about
1000 .mu.mol and [3] whose weight average molecular weight
multiplied by the amount (.mu.mol) of the terminal carboxyl group
per unit mass (g) of the lactic acid-glycolic acid polymer is
1,500,000 to 2,600,000 (inclusive);
[0068] (25) a lactic acid-glycolic acid polymer [1] whose weight
average molecular weight is about 3,000 to about 50,000 and [2]
whose amount (.mu.mol) of the terminal carboxyl group per unit mass
(g) of the lactic acid-glycolic acid polymer is about 20 to about
1000 .mu.mol and [3] whose weight average molecular weight
multiplied by the amount (.mu.mol) of the terminal carboxyl group
per unit mass (g) of the lactic acid-glycolic acid polymer is
1,500,000 to 2,600,000 (inclusive);
[0069] (26) a lactic acid-glycolic acid polymer [1] whose weight
average molecular weight is about 3,000 to about 50,000 and [2]
whose amount (.mu.mol) of the terminal carboxyl group per unit mass
(g) of the lactic acid-glycolic acid polymer is about 40 to about
1000 .mu.mol and [3] whose weight average molecular weight
multiplied by the amount (.mu.mol) of the terminal carboxyl group
per unit mass (g) of the lactic acid-glycolic acid polymer is
1,500,000 to 2,600,000 (inclusive);
[0070] (27) a lactic acid-glycolic acid polymer [1] whose weight
average molecular weight is about 20,000 to about 50,000 and [2]
whose amount (.mu.mol) of the terminal carboxyl group per unit mass
(g) of the lactic acid-glycolic acid polymer is about 20 to about
1000 .mu.mol and [3] whose weight average molecular weight
multiplied by the amount (.mu.mol) of the terminal carboxyl group
per unit mass (g) of the lactic acid-glycolic acid polymer is
1,500,000 to 2,600,000 (inclusive); and,
[0071] (28) a lactic acid-glycolic acid polymer [1] whose weight
average molecular weight is about 20,000 to about 50,000 and [2]
whose amount (.mu.mol) of the terminal carboxyl group per unit mass
(g) of the lactic acid-glycolic acid polymer is about 40 to about
1000 .mu.mol and [3] whose weight average molecular weight
multiplied by the amount (.mu.mol) of the terminal carboxyl group
per unit mass (g) of the lactic acid-glycolic acid polymer is
1,500,000 to 2,600,000 (inclusive).
[0072] A weight average molecular weight, a number average
molecular weight and a polydispersity mean a molecular weight as
polystyrene determined by a gel permeation chromatography (GPC)
using as standards 15 monodisperse polystyrenes whose weight
average molecular weights are 1,110,000, 707,000, 455,645, 354,
000, 189, 000, 156,055, 98, 900, 66, 437, 37, 200, 17, 100, 9,830,
5,870, 2,500, 1,303 and 504 and a polydispersity calculated
therefrom. The determination is performed using a high speed GPC
instrument (TOSO, HLC-8120GPC, detection by differential refractive
index) together with a GPC column KF804Lx2 (SHOWA DENKO) and
chloroform as a mobile phase. The flow rate is 1 ml/min.
[0073] An amount of a free carboxyl group mentioned here means an
amount determined by a labeling method (hereinafter referred to as
a labeling method-based carboxyl group level). Typically, in the
case of a polylactic acid, W mg of the polylactic acid is dissolved
in 2 ml of a mixture of 5N hydrochloric acid/acetonitrile
(v/v=4/96) and combined with 2 ml of a 0.01 M solution of
o-nitrophenylhydrazine hydrochloride (ONPH) (5N hydrochloric
acid/acetonitrile/ethanol=1.02/35/15) and 2 ml of a 0.15M solution
of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride
(pyridine/ethanol=4v/96v), and after allowing the mixture to react
at 40.degree. C. for 30 minutes and then the solvent is distilled
off. The residue is washed with water (4 times), dissolved in 2 ml
of acetonitrile, combined with 1 ml of a 0.5 mol/L ethanolic
solution of potassium hydroxide, and allowed to react at 60.degree.
C. for 30 minutes. The reaction mixture is diluted with a 1.5 N
aqueous solution of sodium hydroxide to make Y ml, which is
examined for the absorbance at 544 nm A(/cm) using a 1.5 N aqueous
solution of sodium hydroxide as a reference standard. On the other
hand, a n aqueous solution of DL-lactic acid is used as a standard
to examine for its free carboxyl group C mol/L by means of an
alkali titration, and subjected to an ONPH labeling method to
convert into DL-lactic acid hydrazide, which is then examined for
the absorbance at 544 nm B(/cm), based on which the molar amount of
the free carboxyl group per unit mass)g) of the polymer is
calculated in accordance with the following equation.
[COOH]=(mol/g)=(AYC)/(WB)
[0074] This "amount of the carboxyl group" can be obtained also by
dissolving a lactic acid-glycolic acid polymer in a solvent mixture
of toluene-acetone-methanol and titrating the resultant solution
for the carboxyl group with an alcoholic solution of potassium
hydroxide using phenolphthalein as an indicator (hereinafter a
value obtained by this method is referred to as "alkali
titration-based carboxyl group level").
[0075] Since the rate at which a lactic acid-glycolic acid polymer
is degraded and disappears is reduced usually at a reduced ratio of
glycolic acid although it may vary greatly depending on the
copolymer composition, the molecular weight or the free carboxyl
group level, it is possible to prolong the release duration by
means of reducing the glycolic acid ratio or increasing the
molecular weight simultaneously with reducing the free carboxyl
group level.
[0076] Such "lactic acid-glycolic acid polymer" can be produced for
example by a non-catalytic dehydrative condensation polymerization
(JP-A-61-28521) from lactic acid and glycolic acid or by a
ring-opening polymerization from cyclic diester compounds such as
lactides and glycolides (Encyclopedic Handbook of Biomaterials and
Bioengineering Part A: Materials, Volume 2, Marcel Dekker, Inc,
1995). While a polymer obtained by the known ring-opening
polymerization described above may sometimes be a polymer having no
free carboxyl group at its terminal, such polymer can be converted
into a polymer having a certain amount of the carboxyl group per
unit mass for example by means of hydrolysis described in
EP-A-0839525 prior to its use.
[0077] "Lactic acid-glycolic acid polymer having a terminal free
carboxyl group" can readily be produced by a known method (for
example, a non-catalytic dehydrative condensation polymerization,
JP-A-61-28521) or by the following methods.
[0078] (1) First, a cyclic ester compound is subjected to a
polymerization using a polymerization catalyst in the presence of a
carboxyl-protected hydroxymonocarboxylic acid derivative (e.g.
t-butyl D-lactate, benzyl L-lactate) or a carboxyl-protected
hydroxydicarboxylic acid derivative (e.g., dibenzyl tartronate,
di-t-butyl dihydroxyethylmalonate).
[0079] "Carboxyl-protected hydroxymonocarboxylic acid derivative"
or "carboxyl-protected hydroxydicarboxylic acid derivative"
mentioned above may for example be a hydroxycarboxylic acid
derivative whose carboxyl group (--COOH) is amidated (--CONH.sub.2)
or esterified (--COOR), with a hydroxycarboxylic acid derivative
whose carboxyl group (--COOH) is esterified (--COOR) being
preferred.
[0080] R in an ester mentioned here may for example be a C.sub.1-6
alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl and
t-butyl, a C.sub.3-8 cycloalkyl group such as cyclopentyl and
cyclohexyl, a C.sub.6-12 aryl group such as phenyl and
.alpha.-naphthyl, a C.sub.7-14 aralkyl group including a
phenyl-C.sub.1-2 alkyl group such as benzyl and phenethyl or an
.alpha.-naphthyl-C.sub.1-2 alkyl group such as
.alpha.-naphthylmethyl. Among those listed above, a t-butyl group
and a benzyl group are preferred.
[0081] "Cyclic ester compound" mentioned above may for example be a
cyclic compound having at least one ester bond within the ring.
Those which are exemplified typically are a cyclic monoester
compound (lactone) and a cyclic diester compound (lactide).
[0082] "Cyclic monoester compound" mentioned above may for example
be a 4-membered cyclic lactone (.beta.-propiolactone,
.beta.-butyrolactone, .beta.-isovalerolactone, .beta.-caprolactone,
.beta.-isocaprolactone, .beta.-methyl-.beta.-valerolactone and the
like), a 5-membered cyclic lactone (.gamma.-butyrolactone,
.gamma.-valerolactone and the like), a .delta.-membered cyclic
lactone (.delta.-valerolactone and the like), a 7-membered cyclic
lactone (.epsilon.-caprolactone and the like), p-dioxanone,
1,5-dioxepan-2-one and the like.
[0083] "Cyclic diester compound" mentioned above may for example be
a compound represented by Formula: ##STR1## wherein R.sup.1 and
R.sup.2 are the same or different and each denotes a hydrogen atom
or a C.sub.1-6 alkyl group such as methyl, ethyl, n-propyl,
isopropyl, n-butyl and t-butyl), and a lactide wherein R.sup.1 is a
hydrogen atom and R.sup.2 is a methyl group or each of R.sup.1 and
R.sup.2 is a hydrogen atom.
[0084] Those exemplified typically are glycolide, L-lactide,
D-lactide, DL-lactide, meso-lactide, 3-methyl-1,4-dioxane-2,5-dione
(including optical isomers) and the like.
[0085] "Polymerization catalyst" mentioned above may for example be
an organic tin-based catalyst (e.g., tin octylate, di-n-butyltin
dilaurate, tetraphenyltin), an aluminum-based catalyst (e.g.,
triethylaluminum) and a zinc-based catalyst (e.g.,
diethylzinc).
[0086] Aluminum-based and zinc-based catalysts are preferred for
the purpose of removing a solvent easily after a reaction, while a
zinc-based catalyst is preferred for the purpose of ensuring the
safety of residual catalyst if any.
[0087] A solvent for a polymerization catalyst is benzene, hexane,
toluene and the like, with hexane and toluene being preferred
especially.
[0088] "Polymerization method" may be a bulk polymerization in
which a reactant is used as being melted or a solution
polymerization in which a reactant is employed as being dissolved
in a suitable solvent (for example, benzene, toluene, xylene,
decalin, and dimethylformamide). A preferred solvent is toluene,
xylene and the like. While the polymerization temperature is not
limited particularly, a bulk polymerization may employ a
temperature capable of melting a reactant at the initiation of the
reaction or higher, usually 100 to 300.degree. C., and a solution
polymerization usually employs room temperature to 150.degree. C.
with using a condenser for reflux or a pressure-resistant reactor
when the reaction temperature exceeds the boiling point of the
reaction solution. While the polymerization time period may vary
depending on the polymerization temperature, other reaction
conditions and intended polymer characteristics, it may for example
be 10 minutes to 72 hours.
[0089] After the reaction, the reaction mixture is dissolved in a
suitable solvent (for example, acetone, dichloromethane,
chloroform), combined with an acid (for example, hydrochloric acid,
acetic anhydride, trifluoroacetic acid) to terminate the
polymerization, and then precipitated for example by mixing with a
solvent which does not dissolve an intended product (for example,
alcohol, water, ether, isopropyl ether) in accordance with a
standard method, whereby isolating a lactic acid-glycolic acid
polymer having a protected carboxyl group at its
.omega.-terminal.
[0090] A polymerization method according to the invention employs a
carboxyl-protected hydroxycarboxylic acid derivative (e.g., t-butyl
D-lactate, benzyl L-lactate) or a carboxyl-protected
hydroxydicarboxylic acid derivative (e.g., dibenzyl tartronate,
di-t-butyl dihydroxyethylmalonate) instead of a protonic chain
transfer agent such as methanol employed conventionally.
[0091] By using such carboxyl-protected hydroxycarboxylic acid
derivative (e.g., t-butyl D-lactate, benzyl L-lactate) or
carboxyl-protected hydroxydicarboxylic acid derivative (e.g.,
dibenzyl tartronate, di-t-butyl dihydroxyethylmalonate) as a
protonic chain transfer agent, [1] it is possible to control the
molecular weight on the basis of the input composition, and [2] a
deprotection after the polymerization serves to make the carboxyl
group free at the .omega.-terminal of the resultant lactic
acid-glycolic acid polymer.
[0092] (2) Subsequently, a lactic acid-glycolic acid polymer having
a protected carboxyl group at its .omega.-terminal obtained by the
polymerization in above-mentioned (1) is deprotected to obtain an
intended lactic acid-glycolic acid polymer having a free carboxyl
group at its .omega.-terminal.
[0093] A protecting group can be deprotected by a method known per
se. While the method may be any method as long as it can remove the
protective group without affecting the ester bond of a
poly(hydroxycarboxylic acid) adversely, it may typically be a
reduction, an acid decomposition and the like.
[0094] A reduction method may for example be a catalytic
hydrogenation using a catalyst (e.g., palladium on carbon,
palladium black, platinum oxide), a reduction with sodium in a
liquid ammonium and a reduction with dithiothreitol. In the case
for example that a polymer having a carboxyl group protected by a
benzyl group at its .omega.-terminal is hydrogenated catalytically,
the polymer dissolved typically in ethyl acetate, dichloromethan,
chloroform and the like is combined with a palladium on carbon,
bubbled with hydrogen with stirring vigorously at room temperature
for about 20 minutes to about 4 hours, whereby accomplishing
deprotection.
[0095] An acid decomposition may for example be an acid
decomposition using an inorganic acid (e.g., hydrogen fluoride,
hydrogen bromide, hydrogen chloride) or an organic acid (e.g.,
trifluoroacetic acid, methanesulfonic acid,
trifluoromethanesulfonic acid) as well as a mixture thereof. If
necessary, the acid decomposition may be performed in the presence
of a cation scavenger (e.g., anisol, phenol, thioanisol). In the
case for example that a polymer having a carboxyl group protected
by a t-butyl group at its .omega.-terminal is subjected to an acid
decomposition, the polymer dissolved typically in dichloromethane,
xylene, toluene and the like is combined with trifluoroacetic acid
in an appropriate amount or the polymer is dissolved in
trifluoroacetic acid, and then the mixture is stirred at room
temperature for about 1 hour, whereby accomplishing
deprotection.
[0096] Preferably, an acid decomposition may also be conducted
immediately after a polymerization reaction, and in such case it
serves also as a polymerization termination reaction.
[0097] Also if necessary, a lactic acid-glycolic acid polymer
obtained by a deprotection described above can be subjected to an
acid hydrolysis to adjust the weight average molecular weight, the
number average molecular weight or the terminal carboxyl group
level as intended. Typically, a method described in EP-A-0839525 or
a method in accordance therewith may be employed.
[0098] A lactic acid-glycolic acid polymer obtained as described
above can be used as a base for producing a sustained release
formulation.
[0099] A polymer having a non-specific free carboxyl group at its
terminal can be produced by a known method (for example, see
WO94/15587).
[0100] Furthermore, a lactic acid-glycolic acid polymer whose
terminal has been converted into a free carboxyl group by means of
a chemical treatment after a ring-opening polymerization is
available commercially for example from Boehringer Ingelheim
KG.
[0101] A lactic acid-glycolic acid polymer may be present as a salt
(such as those listed above), which can be produced for example by
(a) a method in which a lactic acid-glycolic acid polymer having a
carboxyl group described above dissolved in an organic solvent is
combined with an aqueous solution containing an inorganic base
(e.g., an alkaline metal such as sodium and potassium, an alkaline
earth metal such as calcium and magnesium) or with an organic base
(e.g., an organic amine such as triethylamine, a basic amino acid
such as arginine) to effect an ion exchanging reaction, followed by
an isolation of the polymer as a salt, (b) a method in which a weak
acid salt of a base listed in above-mentioned (a) (for example,
acetate and glycolate) is dissolved in a solution of a lactic
acid-glycolic acid polymer having a carboxyl group described above
in an organic solvent and then the lactic acid-glycolic acid
polymer in the form of a salt is isolated, (c) a method in which a
lactic acid-glycolic acid polymer having a carboxyl group described
above dissolved in an organic solvent is combined with a weak acid
salt (for example, acetate and glycolate) or an oxide of a
transition metal (e.g., zinc, iron, copper) and then the lactic
acid-glycolic acid polymer in the form of a salt is isolated.
[0102] While the weight ratio of a pharmacologically active
substance in a composition of the invention may vary depending on
the type of the pharmacologically active substance, the
pharmacological effects desired and the duration thereof, it is
about 0.001 to about 50% by weight, preferably about 0.02 to about
40% by weight, more preferably about 0.1 to about 30% by weight,
most preferably 12 to 24% by weight in the case of a
physiologically active peptide or its salt based on the total
amount of the physiologically active substance or its salt, a
hydroxynaphthoic acid or its salt and a lactic acid-glycolic acid
polymer or its salt when latter three components are contained in a
sustained release composition, and about 0.01 to about 80% by
weight, preferably about 0.1 to about 50% by weight in the case of
a non-peptide physiologically active substance or its salt. Similar
ranges of the weight ratio are applicable even when a
physiologically active substance and a hydroxynaphthoic acid are
contained. In the case of a sustained release composition
comprising a salt of a physiologically active peptide (designated
here as (A)) with a hydroxynaphthoic acid (designated here as (B)),
the weight ratio of (A) based on the total amount of (A)+(B) is
usually about 5 to about 90% by weight, preferably about 10 to
about 85% by weight, more preferably about 15 to about 80% by
weight, especially about 30 to about 80% by weight.
[0103] In the case of a sustained release composition containing
three components, namely, a physiologically active substance or its
salt, a hydroxynaphthoic acid or its salt and a lactic
acid-glycolic acid polymer or its salt, the amount of the
hydroxynaphthoic acid or its salt per 1 mole of the physiologically
active substance or its salt is about 1/2 to about 2 moles,
preferably about 3/4 to about 4/3 moles, especially about 4/5 to
about 6/5 moles.
[0104] A procedure for designing a composition of the invention is
discussed below with referring to a sustained release composition
containing three components, namely, a physiologically active
substance, a hydroxynaphthoic acid and a lactic acid-glycolic acid
polymer in which the physiologically active substance is a basic
substance. In this case, the composition contains the physiological
active substance as a base and the hydroxynaphthoic acid as an
acid, each of which establishes its dissociation equilibrium in a
hydrated state or in the presence of a trace amount of water at any
time point during the production of the composition in any case
that it is incorporated as a free form or a salt into the
composition. Since a salt which a slightly water-soluble
hydroxynaphthoic acid forms together with a physiologically active
substance is considered to be slightly water-soluble although the
solubility may vary depending on the physiologically active
substance employed, the dissociation equilibrium serves favorably
for the formation of such slightly water-soluble salt.
[0105] In order to produce a composition containing a basic
physiologically active substance at a high concentration, it is
preferable in view of the dissociation equilibrium discussed above
to protonate almost all of the physiologically active substance to
form a slightly water-soluble salt described above. For this
purpose, it is preferable that a hydroxynaphthoic acid or its salt
in an amount at least almost equivalent to the physiologically
active substance or its salt is incorporated.
[0106] The mechanism by which a physiologically active substance
contained in a composition is released sustainedly is then
discussed below. The physiologically active substance has mostly
been protonated and exists together with an accompanying counter
ion in the composition described above. The counter ion is mainly a
hydroxynaphthoic acid. After an administration of the composition
to a living body, the lactic acid-glycolic acid polymer undergoes a
degradation to form its oligomers and monomers, and each of the
resultant oligomers (lactic acid-glycolic acid oligomers) and
monomers (lactic acid or glycolic acid) surely has one carboxyl
group, which can also serves as a counter ion for the
physiologically active substance. While the physiologically active
substance is released in a manner involving no transfer of an
electric charge, i.e., it is released as a salt accompanied with a
counter ion, transferable counter ion species may for example be
hydroxynaphthoic acids, lactic acid-glycolic acid oligomers (having
transferable molecular weights) and monomers (lactic acid or
glycolic acid).
[0107] When two or more acids are present simultaneously, a salt
with a strong acid is formed predominantly in general, although the
predominance may vary depending on the ratio. With regard to the
pKa of a hydroxynaphthoic acid, the pKa for example of
3-hydroxy-2-naphthoic acid is 2.708 (KAGAKUBINRAN, II, NIPPON
KAGAKUKAI, Published on Sep. 25, 1969). On the other hand, the pKa
of the carboxyl group of a lactic acid-glycolic acid oligomer is
not known, but it can be calculated from the pKa of lactic acid or
glycolic acid (=3.86 or 3.83) in accordance with the principle that
"the change in the free energy by the introduction of a substituent
can be subjected to an approximation on the basis of addition
rule". The contribution of a substituent to a dissociation constant
was determined and can be utilized (Table 4.1, "pKa Prediction for
Organic Acid and Bases", D. D. Perrin, B. Dempsey and E. P.
Sergeant, 1981). The pKas of a hydroxyl group and an ester bond are
represented as follows:
.DELTA.pKa(OH)=-0.90
.DELTA.pKa(ester bond)=-1.7.
[0108] Accordingly, the pKa of a carboxyl group in a lactic
acid-glycolic acid oligomer, when taking the contribution of an
ester bond which is closest to the dissociated group into
consideration, is represented as follows:
[0109] pKa=pKa(lactic acid or glycolic
acid)-.DELTA.pKa(OH)+.DELTA.pKa(ester bond)=3.06 or 3.03.
Accordingly, a hydroxynaphthoic acid is an acid which is stronger
than lactic acid (pKa=3.86), glycolic acid (pKa=3.83) and the
lactic acid-glycolic acid oligomer (pLa=3.83), and thus it is
possible that the salt of the hydroxynaphthoic acid and the
physiologically active substance is formed predominantly in the
composition described above and that the characteristics of the
salt predominantly determines the sustained release profile of the
physiologically active substance from the composition. A
physiologically active substance employed here may for example be a
physiologically active substance mentioned above.
[0110] In this context, the fact that the salt formed from the
hydroxynaphthoic acid with the physiologically active substance is
slightly water-soluble rather than water-insoluble serves favorably
for the sustained release mechanism. Thus, since a predominant
existence of a salt of the hydroxynaphthoic acid which is stronger
than the lactic acid-glycolic acid oligomer and the monomers among
transferable physiologically active substance salts at an early
stage of the release as evident from the discussion on the acid
dissociation constant described above allows the solubility and the
tissue distribution performance of the salt to be determinant
factors of a release rate of the physiologically active substance,
the initial release pattern of the substance can be adjusted on the
basis of the amount of the hydroxynaphthoic acid to be added.
Subsequently, a decrease in the hydroxynaphthoic acid and an
increase in the oligomers and the monomers formed as a result of
the hydrolysis of the lactic acid-glycolic acid polymer leads to a
gradual predominance of the release mechanism of the
physiologically active substance whose counter ions are the
oligomers and the monomers, whereby maintaining a stable release of
the physiologically active substance even after the
hydroxynaphthoic acid is depleted substantially from "composition"
described above. An increased efficiency in incorporating the
physiologically active substance during the manufacturing process
of the sustained release composition and an ability of suppressing
an initial excessive release after an administration of the
physiologically active substance incorporated can similarly be
explained.
[0111] Also explained similarly by the mechanism described above is
a role of a hydroxynaphthoic acid in a sustained release
composition containing a hydroxynaphthoate of a physiologically
active peptide.
[0112] The term "water-insoluble" used here means that the mass of
a substance dissolved in 1 L of a solution after stirring said
substance at a temperature of 40.degree. C. or lower in distilled
water for 4 hours is 25 mg or less.
[0113] The term "slightly water-insoluble" used herein means that
the mass described above is greater than 25 mg and not greater than
5 g. When the relevant substance is a salt of a physiologically
active substance, then the mass of the physiologically active
substance dissolved in the procedure described above is subjected
to the definition described above.
[0114] While the morphology of a sustained release composition in
the invention is not limited particularly, it is preferably a
microparticle, especially a microsphere (also referred to as a
microcapsule in the case of a sustained release composition
containing a lactic acid-glycolic acid polymer). A microsphere
mentioned here means an injectable spherical microparticle capable
of being dispersed in a solution. The morphology can be verified
for example by an observation using a scanning electron
microscope.
[0115] A method for producing a an inventive sustained release
composition comprising a pharmacologically active substance or its
salt, a hydroxynaphthoic acid or its salt and a lactic
acid-glycolic acid polymer or its salt is described below with
exemplifying a microcapsule.
(I) In-Water Drying Method
(i) O/W Method
[0116] In this method, a solution of a hydroxynaphthoic acid or its
salt and a lactic acid-glycolic acid polymer or its salt in an
organic solvent is prepared first. An organic solvent used for
producing an inventive sustained release formulation preferably has
a melting point of 120.degree. C. or lower.
[0117] Such organic solvent may for example be a halogenated
hydrocarbon (e.g., dichloromethane, chloroform, dichloroethane,
trichloroethane, carbon tetrachloride), an ether (e.g., ethyl
ether, isopropyl ether), a fatty acid ester (e.g., ethyl acetate,
butyl acetate), an aromatic hydrocarbon (e.g., benzene, toluene,
xylene), an alcohol (e.g., ethanol, methanol) as well as
acetonitrile. As an organic solvent for a lactic acid-glycolic acid
polymer or its salt, dichloromethane is especially preferred.
[0118] As an organic solvent for the hydroxynaphthoic acid or its
salt, an alcohol or a mixture of an alcohol and a halogenated
hydrocarbon is especially preferred.
[0119] The hydroxynaphthoic acid or its salt and the lactic
acid-glycolic acid polymer or its salt may be dissolved separately
and then mixed with each other, or the both may be dissolved in an
organic solvent mixture at a certain ratio. Among the solvents, a
mixture of a halogenated hydrocarbon and an alcohol is employed
preferably, with a mixture of dichloromethane and ethanol being
preferred particularly.
[0120] The ethanol content in an organic solvent mixture of
dichloromethane and ethanol when using ethanol as an organic
solvent to be mixed with dichloromethane is usually about 0.01 to
about 50% (v/v), more preferably about 0.05 to about 40% (v/v),
especially about 0.1 to about 30% (v/v).
[0121] While the concentration of the lactic acid-glycolic acid
polymer in an organic solvent solution may vary depending on the
molecular weight of the lactic acid-glycolic acid polymer and the
type of the organic solvent, it is usually about 0.5 to about 70%
by weight, more preferably about 1 to about 60% by weight,
especially about 2 to about 50% by weight, when using
dichloromethane as an organic solvent.
[0122] The concentration of the hydroxynaphthoic acid or its salt
in an organic solvent, when using a mixture of dichloromethane and
ethanol as an organic solvent, is usually about 0.01 to about 10%
by weight, more preferably about 0.1 to about 5% by weight,
especially about 0.5 to about 3% by weight.
[0123] To the solution of the hydroxynaphthoic acid or its salt and
the lactic acid-glycolic acid polymer thus obtained, a
pharmacologically active substance or its salt is added and
dissolved or dispersed. Then, the resultant organic solvent
solution containing a composition consisting of the
pharmacologically active substance or its salt, the
hydroxynaphthoic acid or its salt and the lactic acid-glycolic acid
polymer is added to an aqueous phase to form an O(oil
phase)/W(aqueous phase) emulsion, and then the solvent in the oil
phase is evaporated or dispersed in the aqueous phase, whereby
preparing a microcapsule. The volume of this aqueous phase is
usually about 1 to about 10,000 times, more preferably about 5 to
about 50,000 times, especially about 10 to about 2,000 times the
volume of the oil phase.
[0124] The outer aqueous phase described above may contain an
emulsifier. Such emulsifier may usually be any emulsifier capable
of forming a stable O/W emulsion. One employed typically is an
anionic surfactant (sodium oleate, sodium stearate, sodium
laurylsulfate and the like), a nonionic surfactant (polyoxyethylene
sorbitan fatty acid ester [polyoxyethylene 20 sorbitan monooleate
sold under the trademark Tween.RTM. 80, polyoxyethylene sorbitan
monostearate sold under the trademark Tween.RTM. 60, available from
"ATRASPOWDER"], a polyoxyethylene castor oil derivative
[polyethylene glycol (PEG)-60 hydrogenated castor oil sold under
the trademark NIKKOL.TM. HCO-60, polyethylene glycol (PEG)-50
hydrogenated castor oil sold under the trademark NIKKOL.TM. HCO-50,
available from "NIKKO CHEMICALS"]), polyvinylpyrrolidone, polyvinyl
alcohol, carboxymethyl cellulose, lecithin, gelatin, hyaluronic
acid and the like. Any of those listed above may be employed alone
or in combination with each other. The concentration is preferably
about 0.0001 to about 10% by weight, more preferably about 0.001 to
about 5% by weight.
[0125] To the outer aqueous phase, an osmotic agent may be
added.
[0126] This osmotic agent may be any substance giving an osmotic
pressure in an aqueous solution thereof.
[0127] Such osmotic agent may for example be polyhydric alcohol,
monohydric alcohol, monosaccharide, disaccharide, oligosaccharide,
amino acid as well as derivatives thereof.
[0128] A polyhydric alcohol mentioned above may for example be a
trihydric alcohol such as glycerin, a pentahydric alcohol such as
arabitol, xylitol and adonitol, a hexahydric alcohol such as
mannitol, sorbitol and dulcitol. Among those listed above, a
hexahydric alcohol is preferred, with mannitol being especially
preferred.
[0129] A monohydric alcohol mentioned above may for example be
methanol, ethanol and isopropyl alcohol, with ethanol being
preferred.
[0130] A monosaccharide mentioned above may for example be a
pentose such as arabinose, xylose, ribose and 2-deoxyribose, a
hexose such as glucose, fructose, galactose, mannose, sorbose,
rhamnose and fucose, with a hexose being preferred.
[0131] An oligosaccharide mentioned above may for example be a
trisaccharide such as maltotriose and raffinose and a
tetrasaccharide such as stachyose, with a trisaccharide being
preferred.
[0132] A derivatives of a monosaccharide, a disaccharide and an
oligosaccharide described above may for example be glucosamine,
galactosamine, glucuronic acid and galacturonic acid.
[0133] An amino acid mentioned above may be any L-amino acid, such
as glycine, leucine and arginine. L-Arginine is preferred.
[0134] Any of these osmotic agents may be employed alone or in
combination with each other.
[0135] Any of these osmotic agents is used at a concentration
giving the osmotic pressure of the outer aqueous phase which is
about 1/50 to about 5 times, preferably about 1/25 to about 3 times
the osmotic pressure of physiological saline.
[0136] A method for removing an organic solvent may be any method
known per se or a method in accordance therewith. For example, the
organic solvent is evaporated at atmospheric pressure or under
incrementally reduced pressure with stirring using a propeller
stirrer, a magnetic stirrer or a ultrasonicating machine, or
evaporated with adjusting the vacuum level using a rotary
evaporator, or evaporated gradually using a dialyzing membrane.
[0137] A microcapsule thus obtained is isolated using a
centrifugation or a filtration, and any free forms of the
physiologically active substance or its salt, the hydroxynaphthoic
acid or its salt, a vehicle, an emulsifier and the like deposited
on the surface of the microcapsule are washed off several times
with distilled water, and then dispersed again in distilled water
and lyophilized.
[0138] During a manufacturing process, an anti-aggregating agent
may be added in order to prevent the aggregation between particles.
Such anti-aggregating agent may for example be a water-soluble
polysaccharide such as mannitol, lactose, glucose and starches
(such as corn starch), an amino acid such as glycine, a protein
such as fibrin and collagen. Among these, mannitol is employed
preferably.
[0139] After a lyophilization, water and the organic solvent
contained in the microcapsule can be removed if necessary under
reduced pressure by warming while avoiding the fusion between the
microcapsules.
[0140] Preferably, the warming is accomplished at a temperature
which is higher slightly than the intermediate glass transition
point of a lactic acid-glycolic acid polymer determined by a
differential scanning calorimeter with raising the temperature by
10 to 20.degree. C. per minutes. The intermediate glass transition
point of a lactic acid-glycolic acid polymer to a temperature
higher by about 30.degree. C. than this temperature is the range of
the temperature at which the warming is accomplished more
preferably. Preferably, the warming is accomplished at a
temperature within the range from the intermediate glass transition
point of a lactic acid-glycolic acid polymer to a temperature which
is higher than the intermediate glass transition point by
10.degree. C., more preferably at a temperature within the range
from the intermediate glass transition point to a temperature which
is higher than the intermediate glass transition point by 5.degree.
C.
[0141] While the time period of the warming may vary depending on
the amount of a microcapsule and the like, it is usually about 12
hours to about 168 hours, preferably about 24 hours to about 120
hours, especially about 48 hours to about 96 hours after the
temperature of the microcapsule itself reached a certain
temperature.
[0142] A method for warming is not limited particularly, as long as
it enables a uniform warming of a microcapsule bulk.
[0143] Such warming method may for example be a method for warming
and drying in a thermostat chamber, a fluidized tank, a mobile tank
or a kiln, or a method for warming and drying with a microwave.
Among these methods, a method for warming and drying in a
thermostat chamber is preferred.
(ii) W/O/W Method (1)
[0144] First, a solution of a lactic acid-glycolic acid polymer or
its salt in an organic solvent is preferred. The organic solvent
and the concentration of the lactic acid-glycolic acid polymer or
its salt in the organic solvent are similar to those described in
the above-mentioned (I)(I). When an organic solvent mixture is
employed, the ratio is also similar to that described in the
above-mentioned (I)(i).
[0145] To a solution of the lactic acid-glycolic acid polymer or
its salt in an organic solvent thus obtained, a physiologically
active substance or its salt is added and dissolved or dispersed.
Then the resultant organic solvent solution (oil phase) containing
a composition consisting of the physiologically active substance or
its salt and the lactic acid-glycolic acid polymer or its salt is
combined with a solution of a hydroxynaphthoic acid or its salt [in
the solvent such as water, an aqueous solvent such as an alcohol
(e.g., methanol, ethanol), an aqueous solution of pyridine, an
aqueous solution of dimethylacetoamide]. The mixture is emulsified
by a known method for example using a homogenizer or a
ultrasonication to form a W/O emulsion.
[0146] Then the resultant W/O emulsion consisting of the
physiologically active substance or its salt, the hydroxynaphthoic
acid or its salt and the lactic acid-glycolic acid polymer or its
salt is added to an aqueous phase to form a W(inner aqueous
phase)/O(oil phase)/W(outer aqueous phase) emulsion, and then the
solvent in the oil phase is evaporated to prepare a microcapsule.
The volume of this outer aqueous phase is usually about 1 to about
10,000 times, more preferably about 5 to about 5,000 times,
especially about 10 to about 2,000 times the volume of the oil
phase.
[0147] An emulsifier and an osmotic agent which may be added to an
outer aqueous phase described above and the subsequent preparation
are similar to those described in the above-mentioned (I) (i).
(iii) W/O/W Method (2)
[0148] First, a solution of a hydroxynaphthoic acid or its salt and
a lactic acid-glycolic acid polymer or its salt in an organic
solvent is prepared, and the resultant organic solvent solution is
referred to as an oil phase. This production method is similar to
that described in the above-mentioned (I)(i). Alternatively, the
hydroxynaphthoic acid or its salt and the lactic acid-glycolic acid
polymer or its salt may be formulated separately into organic
solvent solutions, and thereafter the both are mixed. While the
concentration of the lactic acid-glycolic acid polymer in an
organic solvent solution may vary depending on the molecular weight
of the lactic acid-glycolic acid polymer and the type of the
organic solvent, it is usually about 0.5 to about 70% by weight,
more preferably about 1 to about 60% by weight, especially about 2
to about 50% by weight, when using dichloromethane as an organic
solvent.
[0149] Then a solution or a dispersion of a physiologically active
substance or its salt [in the solvent such as water and a mixture
of water and an alcohol (e.g., methanol, ethanol)] is prepared. The
concentration at which the physiologically active solution or its
salt is added is usually 0.001 mg/ml to 10 g/ml, more preferably
0.1 mg/ml to 5 g/ml, particularly 10 mg/ml to 3 g/ml.
[0150] Known solubilizer and stabilizer may be added. For
dissolving or dispersing the physiologically active substance and
the additives, heating, shaking or stirring may be performed as
long as the activity is not lost, and the resultant aqueous
solution is referred to as an inner aqueous phase.
[0151] The inner aqueous phase and the oil phase obtained as
described above is emulsified by a known method for example using a
homogenizer or a ultrasonication to form a W/O emulsion.
[0152] The volume of the oil phase to be mixed is usually about 1
to about 1,000 times, more preferably about 2 to about 100 times,
especially about 3 to about 10 times the volume of the inner water
phase.
[0153] The resultant W/O emulsion is usually about 10 to about
10,000 cps, preferably about 100 to about 5,000 cps at about 12 to
about 20.degree. C.
[0154] Then the resultant W/O emulsion consisting of the
physiologically active substance or its salt, the hydroxynaphthoic
acid or its salt and the lactic acid-glycolic acid polymer or its
salt is added to an aqueous phase to form a W(inner aqueous
phase)/O(oil phase)/W(outer aqueous phase) emulsion, and then the
solvent in the oil phase is evaporated or diffused into the outer
aqueous phase, whereby preparing a microcapsule. The volume of this
outer aqueous phase is usually about 1 to about 10,000 times, more
preferably about 5 to about 50,000 times, especially about 10 to
about 2,000 times the volume of the oil phase. An emulsifier and an
osmotic agent which may be added to an outer aqueous phase
described above and the subsequent preparation are similar to those
described in the above-mentioned (I) (i).
(II) Phase Separation Method
[0155] When a microcapsule is prepared by this method, a
coacervating agent is added portionwise with stirring to a solution
of a composition consisting of a pharmacologically active substance
or its salt, a hydroxynaphthoic acid or its salt and a lactic
acid-glycolic acid polymer or its salt in an organic solvent
described in the in-water drying method of the above-mentioned (I)
to precipitate and solidify the microcapsule. Such coacervating
agent is about 0.01 to about 1,000 times, preferably about 0.05 to
about 500 times, particularly about 0.1 to about 200 times the
volume of the oil phase.
[0156] A coacervating agent is not particularly limited as long as
it is a polymeric, mineral or vegetable compound miscible with an
organic solvent and it does not allow a complex of a
physiologically active substance or its salt with a
hydroxynaphthoic acid or its salt and a lactic acid-glycolic acid
polymer or its salt to be dissolved. Those exemplified typically
are silicon oil, sesame oil, soybean oil, corn oil, cottonseed oil,
coconut oil, linseed oil, mineral oils, n-hexane, n-heptane and the
like. Any of these substance may be employed alone or in
combination with each other.
[0157] The microcapsule thus obtained is isolated, washed
repetitively for example with heptane to make the composition
consisting of the pharmacologically active substance or its salt,
the hydroxynaphthoic acid or its salt and the lactic acid-glycolic
acid polymer or its salt free of the coacervating agent and other
material, and then dried under reduced pressure. Alternatively, the
washing is performed by the method similar to that described in the
in-water drying method in the above-mentioned (I)(i), and then a
lyophilizaiton followed by a drying with warming is performed.
(III) Spray-Drying Method
[0158] When a microcapsule is prepared by this method, a solution
comprising a pharmacologically active substance or its salt, a
hydroxynaphthoic acid or its salt and a lactic acid-glycolic acid
polymer or its salt in an organic solvent described in the in-water
drying method of the above-mentioned (I) is sprayed via a nozzle
into a drying chamber of a spray drier, whereby evaporating the
organic solvent in a microparticulate droplet within an extremely
short period to prepare a microcapsule. Such nozzle may for example
be a dual-fluid nozzle, a pressure nozzle, a rotating disc nozzle
and the like. Subsequently, the washing is performed if necessary
by the method similar to that described in the in-water drying
method in the above-mentioned (I) and then a lyophilizaiton
followed by a drying with warming is performed.
[0159] A microcapsule dosage form other than the microcapsule
described above can be prepared by subjecting a solution comprising
a pharmacologically active substance or its salt, a
hydroxynaphthoic acid or its salt and a lactic acid-glycolic acid
polymer or its salt in an organic solvent described in the in-water
drying method of the above-mentioned microcapsule production method
(I) for example to a rotary evaporator, where the organic solvent
and water are evaporated into dryness with controlling the vacuum
level, followed by a pulverization using a jet mill and the like,
whereby obtaining a fine powder (also referred to as a
microparticle).
[0160] Thereafter, the pulverized fine powder may be washed by the
method similar to that described in the in-water drying method in
the above-mentioned microcapsule production method (I) and then a
lyophilizaiton followed by a drying with warming is performed.
[0161] A microcapsule or a fine powder obtained here enables a
medicament release corresponding to the degradation rate of a
lactic acid-glycolic acid polymer employed.
[0162] A sustained release composition according to the invention
may be any dosage form such as a microsphere, a microcapsule, a
fine powder (microparticle) and the like, it is preferably in the
form of a microcapsule.
[0163] A sustained release composition according to the invention
can be formulated as it is or employed as a starting material to
produce any of various dosage forms, such as an intramuscular,
subcutaneous or tissue injection or implantation formulation, a
nasal, rectal and intrauterine mucosal formulation, an oral
formulation (e.g., solid dosage form such as capsule including hard
and soft capsules, granule and powder, liquid formulation such as
syrup, emulsion and suspension) and the like.
[0164] When a sustained release composition according to the
invention is formulated into an injection formulation, it is
formulated into an aqueous suspension together with a dispersing
agent (e.g., surfactant such as Tween 80 and HCO-60, polysaccharide
such as sodium hyaluronate, carboxymethyl cellulose, sodium
arginate and the like), a preservative (e.g., methylparaben,
propylparaben), an isotonic agent (e.g., sodium chloride, mannitol,
sorbitol, glucose, proline), or dispersed together with a vegetable
oil such as sesame oil and corn oil to prepare an oily suspension,
whereby obtaining a practically utilizable sustained release
injection formulation.
[0165] The particle size of a sustained release composition when
employed as a suspension injection formulation becomes acceptable
when it allows the dispersing performance and the passage through
the syringe needle to be satisfactory, and the mean particle size
may for example be about 0.1 to about 300 .mu.m, preferably about
0.5 to about 150 .mu.m, more preferable about 1 to about 100
.mu.m.
[0166] An aseptic formulation of a sustained release composition
according to the invention can be obtained for example by a method
in which the entire manufacturing process is performed aseptically,
a method utilizing a sterilization with a gamma ray or a method in
which a preservative is added, although there is no particular
limitation.
[0167] Since a sustained release composition according to the
invention has a low toxicity, it can be used as a safe
pharmaceutical in a mammal (e.g., human, cattle, swine, dog, cat,
mouse, rat, rabbit).
[0168] While the dose of a sustained release composition according
to the invention may vary depending on the type and the content of
a physiologically active substance as a main ingredient, the dosage
form, the duration of the release of the pharmacologically active
substance, the target disease and the target animal, it may be an
effective amount of the pharmacologically active substance. A
single dose of a pharmacologically active substance as a main
ingredient, when the sustained release formulation is a 6-month
formulation, is preferably about 0.01 mg to about 10 mg/kg body
weight a day in an adult, more preferably about 0.05 mg to about 5
mg/kg body weight.
[0169] The single dose of a sustained release composition is
preferably about 0.05 mg to about 50 mg/kg body weight in an adult,
more preferably about 0.1 mg to about 30 mg/kg body weight.
[0170] The frequency of the administration may be once in several
weeks, once a month or once in several months (e.g., 3, 4 or 6
months), depending on the type and the content of a physiologically
active substance as a main ingredient, the dosage form, the
duration of the release of the pharmacologically active
substance.
[0171] While a sustained release composition according to the
invention can be used as a prophylactic and therapeutic agent
against various diseases depending on the type of the
pharmacologically active substance contained therein, it, when
containing an LH-RH derivative as a pharmacologically active
substance, can be used as a prophylactic and therapeutic agent
against a hormone-dependent disease, especially a sex
hormone-dependent cancer (e.g., prostate cancer, uterine cancer,
mammary cancer, pituitary cancer and the like), a sex
hormone-dependent disease such as prostate hyperplasia,
endometriosis, hysteromyoma, precocious puberty, dysmenorrhea,
amenorrhea, premenstrual syndrome, multilocular ovarian syndrome
and the like, and useful as a contraceptive (or against infertility
when utilizing a rebound effect after discontinuation). It is also
useful for treating a benign or malignant tumor which is not sex
hormone-dependent but is LH-RH sensitive.
EXAMPLES
[0172] The present invention is further described with referring to
the following Examples and Experiments, which are not intended to
restrict the invention.
Example 1
[0173] A solution of 1.2 g of the acetate of
5-oxo-Pro-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH--C.sub.2H.sub.5
(hereinafter abbreviated as Peptide A, Takeda Chemical Industries,
Ltd.) dissolved in 1.2 ml of distilled water was mixed with a
solution of 4.62 g of a DL-lactic acid polymer (weight average
molecular weight: 40,600, number average molecular weight: 21,800,
terminal carboxyl group level: 52.7 .mu.mol/g) and 0.18 g of
1-hydroxy-2-naphthoic acid dissolved in a solvent mixture of 8.25
ml of dichloromethane and 0.45 ml of ethanol, and emulsified using
a homogenizer to form a W/O emulsion. Then the W/O emulsion was
poured into 1200 ml of a 0.1% (w/w) aqueous solution of a polyvinyl
alcohol (EG-40, Nippon Synthetic Chemical Industry Co., Ltd.) which
had previously been kept at 15.degree. C., and agitated using a
turbine homomixer at 7,000 rpm to form a W/O/W emulsion. This W/O/W
emulsion was stirred at room temperature for 3 hours to allow
dichloromethane and ethanol to be evaporated or diffused into the
outer aqueous layer, and then the oil phase was solidified, sieved
through a 75 .mu.m mesh-sized sieve, centrifuged at 2000 rpm for 5
minutes (05PR-22, Hitachi, Ltd.) to precipitate a microcapsule,
which was then recovered. The microcapsule was dispersed again in
distilled water, centrifuged again, washed to remove free
components and then recovered. To the recovered microcapsule was
added a small amount of distilled water to disperse again. 0.3 g of
mannitol was dissolved therein and then the mixture was lyophilized
to obtain a powder. The % recovery as mass of the microcapsule was
46.91%, and the Peptide A content of the microcapsule was 18.7%
while the 1-hydroxy-2-naphthoic acid content was 2.57%.
Example 2
[0174] A solution of 1.2 g of the acetate of Peptide A dissolved in
1.2 ml of distilled water was mixed with a solution of 4.62 g of a
DL-lactic acid polymer (weight average molecular weight: 40,600,
number average molecular weight: 21,800, terminal carboxyl group
level: 52.7 .mu.mol/g) and 0.18 g of 3-hyroxy-2-naphthoic acid
dissolved in a solvent mixture of 7.5 ml of dichloromethane and
0.45 ml of ethanol, and emulsified using a homogenizer to form a
W/O emulsion. Thereafter, the mixture was treated similarly to
EXAMPLE 1 to obtain a microcapsule powder. The % recovery as mass
of the microcapsule was 53.18%, and the Peptide A content of the
microcapsule was 17.58% while the 3-hydroxy-2-naphthoic acid
content was 2.49%.
Experiment 1
[0175] About 45 mg of each microcapsule obtained in EXAMPLES 1 and
2 was dispersed in 0.3 ml of a dispersion medium (0.15 mg of
carboxymethyl cellulose, 0.3 mg of polysorbate 80, 15 mg of
mannitol dissolved in distilled water), and administered via a 22G
injection needle subcutaneously to a dorsal area of a 7-week old
male SD rat. After a predetermined period, the rat was sacrificed
and the microcapsule remaining at the administration site was taken
out, examined for the Peptide A content, which was divided by the
initial content to obtain a % residue, which is shown in Table 1.
TABLE-US-00002 TABLE 1 % Residue, Peptide A Example 1 Example 2 1
Day 92.9% 93.7% 2 Weeks 74.6% 78.8% 4 Weeks 56.0% 58.0% 8 Weeks
31.6% 36.0% 12 Weeks 28.3% 32.3% 16 Weeks 24.5% 26.8% 20 Weeks
17.8% 23.8% 26 Weeks 12.6% 15.6%
[0176] As evident from Table 1, both of the microcapsule of EXAMPLE
1 containing 1-hydroxy-2-naphthoic acid and the microcapsule of
EXAMPLE 2 containing 3-hydroxy-2-naphthoic acid could contain the
pharmaceutically active substance at high concentrations, and
exhibited an extremely high suppressed effect on the initial
excessive release of the physiologically active substance. Any of
these microcapsules accomplished a sustained release of the
physiologically active substance at a constant rate over an
extremely prolonged period.
Example 3
[0177] A solution of 1.2 g of the acetate of Peptide A dissolved in
1.2 ml of distilled water was mixed with a solution of 4.62 g of a
DL-lactic acid polymer (weight average molecular weight: 32,000,
number average molecular weight: 17,800, terminal carboxyl group
level: 72.1 .mu.mol/g) and 0.18 g of 3-hyroxy-2-naphthoic acid
dissolved in a solvent mixture of 7.5 ml of dichloromethane and
0.45 m of ethanol, and emulsified using a homogenizer to form a W/O
emulsion. Thereafter, the mixture was treated similarly to EXAMPLE
1 to obtain a microcapsule powder. The % recovery as mass of the
microcapsule was 51.2%, and the Peptide A content of the
microcapsule was 18.05% while the 3-hydroxy-2-naphthoic acid
content was 2.42%.
Experiment 2
[0178] About 250 mg of the microcapsule obtained in EXAMPLE 3 was
dispersed in 1.5 ml of a dispersion medium (0.75 mg of
carboxymethyl cellulose, 1.5 mg of polysorbate 80, 75 mg of
mannitol dissolved in distilled water), and administered via a 22G
injection needle intramuscularly to a rump area of a beagle. One
the other hand, about 125 mg of this microcapsule was dispersed in
0.75 ml of a dispersion medium (0.375 mg of carboxymethyl
cellulose, 0.75 mg of polysorbate 80, 37.5 mg of mannitol dissolved
in distilled water), and administered via a 22G injection needle
subcutaneously to a rump area of a beagle. After a predetermined
period, a blood was taken from a forearm vein and examined for the
serum levels of Peptide A and testosterone, which are shown in
Table 2. TABLE-US-00003 TABLE 2 Peptide A (ng/ml) Testosterone
(ng/ml) Intramuscular administration 1 Day 7.33 5.31 2 Weeks 0.76
0.46 4 Weeks 0.91 0.58 8 Weeks 3.65 0.25 or less 12 Weeks 1.56 0.25
or less 16 Weeks 1.14 0.25 or less 20 Weeks 0.59 0.25 or less 26
Weeks 0.53 0.25 or less 28 Weeks 0.48 0.25 or less 30 Weeks 0.33
0.26 32 Weeks 0.37 0.79 34 Weeks 0.22 1.41 36 Weeks 0.14 0.94
Subcutaneous administration 1 Day 17.61 2.79 2 Weeks 0.99 1.95 4
Weeks 0.62 1.50 8 Weeks 0.76 0.68 12 Weeks 1.77 0.25 or less 16
Weeks 1.57 0.25 or less 20 Weeks 1.23 0.25 or less 26 Weeks 1.93
0.33 28 Weeks 0.35 1.59 30 Weeks 0.25 2.00
[0179] As evident from Table 2, the blood level of the
physiologically active substance was maintained over a period as
long as about 26 weeks, during which the testosterone level as an
index of the efficacy was kept at a normal level or lower, and then
began to recover a normal level over a period of about 28 weeks to
34 weeks in response to the reduction in the blood level of the
physiologically active substance. Even when a hydroxynaphthoic acid
is contained in the formulation, the physiologically active
substance was present stably in the microcapsule for a prolonged
period without losing its activity whereby being released
sustainedly. It became also evident that the stable efficacy was
exhibited regardless of the administration modes.
Example 4
[0180] A solution of 86.2 g of a DL-lactic acid polymer (weight
average molecular weight: 28,300, number average molecular weight:
14,700, labeling method-based carboxyl group level: 69.2 .mu.mol/g)
dissolved in 67 g of dichloromethane and 87.7 g of a solution
obtained by dissolving 9 g of 3-hydroxy-2-naphthoic acid in 210 g
of dichloromethane and 16.2 g of ethanol were mixed and adjusted at
28.8.degree. C. 219.2 g of this organic solvent solution was
weighed and mixed with an aqueous solution of 20.4 g of the acetate
of Peptide A dissolved in 18.8 g of distilled water kept at
54.8.degree. C., and the mixture was stirred for 5 minutes to
emulsify only crudely, and then emulsified using a homogenizer at
10,000 rpm for 5 minutes to form a W/O emulsion. Then this W/O
emulsion was cooled to 12.7.degree. C. and the poured over a period
of 5 minutes and 11 seconds into 20 L of a 0.1% (w/w) aqueous
solution of a polyvinyl alcohol (EG-40, NIPPON SYNTHETIC CHEMICAL
INDUSTRY CO., LTD.) which had previously been kept at 12.7.degree.
C., and agitated using HOMOMIC LINE FLOW (TOKUSHUKIKAI) at 9,000
rpm to form a W/O/W emulsion. This W/O/W emulsion was adjusted at
15.degree. C. for 30 minutes, and then stirred without adjusting
the temperature for 2 hours and 30 minutes to allow dichloromethane
and ethanol to be evaporated or diffused into the outer aqueous
layer, and then the oil phase was solidified, sieved through a 75
.mu.m mesh-sized sieve, centrifuged at 2000 rpm continuously
(H-600S, KOKUSANENSHINKI) to precipitate a microcapsule, which was
then recovered. The recovered microcapsule was dispersed again in a
small amount of distilled water, and sieved through a 90 .mu.m
mesh-sized sieve. 12.3 g of mannitol was dissolved therein and then
the mixture was lyophilized to obtain a powder. The yield as mass
of the microcapsule was 84.4 g, which corresponded to the %
recovery of 75.7%, and the Peptide A content was 17.8% while the
3-hydroxy-2-naphthoic acid content was 2.5%.
Example 5
[0181] A solution of 107.8 g of a DL-lactic acid polymer (weight
average molecular weight:27,700, number average molecular
weight:15,700, labeling method-based carboxyl group level:69.8
.mu.mol/g) dissolved in 83.9 g of dichloromethane and 110.2 g of a
solution obtained by dissolving 7.5 g of 1-hydroxy-2-naphthoic acid
in 175.8 g of dichloromethane and 13.5 g of ethanol were mixed and
adjusted at 28.2.degree. C. 274.2 g of this organic solvent
solution was weighed and mixed with an aqueous solution of 25.6 g
of the acetate of Peptide A dissolved in 23.52 g of distilled water
kept at 52.4.degree. C., and the mixture was stirred for 5 minutes
to emulsify only crudely, and then emulsified using a homogenizer
at 10,080 rpm for 5 minutes to form a W/O emulsion. Then this W/O
emulsion was cooled to 12.5.degree. C. and the poured over a period
of 3 minutes and 42 seconds into 25 L of a 0.1% (w/w) aqueous
solution of a polyvinyl alcohol (EG-40, NIPPON SYNTHETIC CHEMICAL
INDUSTRY CO., LTD.) which had previously been kept at 13.1.degree.
C., and agitated using HOMOMIC LINE FLOW (TOKUSHUKIKAI) at 7,000
rpm to form a W/O/W emulsion. This W/O/W emulsion was adjusted at
15.degree. C. for 30 minutes, and then stirred without adjusting
the temperature for 2 hours and 30 minutes to allow dichloromethane
and ethanol to be evaporated or diffused into the outer aqueous
layer, and then the oil phase was solidified, sieved through a 75
.mu.m mesh-sized sieve, centrifuged at 2000 rpm continuously
(H-600S, KOKUSANENSHINKI) to precipitate a microcapsule, which was
then recovered. The recovered microcapsule was dispersed again in a
small amount of distilled water, and sieved through a 90 .mu.m
mesh-sized sieve. 15.4 g of mannitol was dissolved therein and then
the mixture was lyophilized to obtain a powder. The yield as mass
of the microcapsule was 105.7 g, which corresponded to the %
recovery of 75.8%, and the Peptide A content was 17.8% while the
1-hydroxy-2-naphthoic acid content was 2.8%.
Example 6
[0182] A solution of 107.6 g of a DL-lactic acid polymer (weight
average molecular weight: 30,800, number average molecular weight:
13,900, labeling method-based carboxyl group level: 66.3 .mu.mol/g)
dissolved in 83.3 g of dichloromethane and 109.7 g of a solution
obtained by dissolving 7.5 g of 1-hydroxy-2-naphthoic acid in 175 g
of dichloromethane and 13.5 g of ethanol were mixed and adjusted at
28.7.degree. C. 274.3 g of this organic solvent solution was
weighed and mixed with an aqueous solution of 24.89 g of the
acetate of Peptide A dissolved in 23.49 g of distilled water kept
at 51.2.degree. C., and the mixture was stirred for 5 minutes to
emulsify only crudely, and then emulsified using a homogenizer at
10,070 rpm for 5 minutes to form a W/O emulsion. Then this W/O
emulsion was cooled to 12.8.degree. C. and the poured over a period
of 4 minutes and 13 seconds into 25 L of a 0.1% (w/w) aqueous
solution of a polyvinyl alcohol (EG-40, NIPPON SYNTHETIC CHEMICAL
INDUSTRY CO., LTD.) which had previously been kept at 13.3.degree.
C., and agitated using HOMOMIC LINE FLOW (TOKUSHUKIKAI) at 7,000
rpm to form a W/O/W emulsion. This W/O/W emulsion was adjusted at
15.degree. C. for 30 minutes, and then stirred without adjusting
the temperature for 2 hours and 30 minutes to allow dichloromethane
and ethanol to be evaporated or diffused into the outer aqueous
layer, and then the oil phase was solidified, sieved through a 75
.mu.m mesh-sized sieve, centrifuged at 2000 rpm continuously
(H-600S, KOKUSANENSHINKI) to precipitate a microcapsule, which was
then recovered. The recovered microcapsule was dispersed again in a
small amount of distilled water, and sieved through a 90 .mu.m
mesh-sized sieve. 15.4 g of mannitol was dissolved therein and then
the mixture was lyophilized to obtain a powder. The yield as mass
of the microcapsule was 101.9 g, which corresponded to the %
recovery of 73.1%, and the Peptide A content was 17.3% while the
1-hydroxy-2-naphthoic acid content was 2.9%.
Experiment 3
[0183] About 45 mg of each microcapsule obtained in EXAMPLES 5 and
6 was dispersed in 0.3 ml of a dispersion medium (0.15 mg of
carboxymethyl cellulose, 0.3 mg of polysorbate 80, 15 mg of
mannitol dissolved in distilled water), and administered via a 22G
injection needle subcutaneously to a dorsal area of a 7-week old
male SD rat. After a predetermined period, the rat was sacrificed
and the microcapsule remaining at the administration site was taken
out, examined for the Peptide A content, which was divided by the
initial content to obtain a % residue, which is shown in Table 3.
TABLE-US-00004 TABLE 3 % Residue, Peptide A Example 5 Example 6 1
Day 87.0% 90.5% 1 Week 80.0% 83.2% 2 Weeks 72.3% 73.5% 4 Weeks
57.6% 58.0% 8 Weeks 48.2% 46.7% 12 Weeks 34.5% 32.8% 16 Weeks 23.1%
22.0% 20 Weeks 14.7% 13.4% 26 Weeks 6.1% 3.3%
[0184] As evident from Table 3, both of the microcapsules of
EXAMPLES 5 and 6 containing 1-hydroxy-2-naphthoic acid, which
differed in the molecular weight of the lactic acid polymer as a
base, could contain the pharmaceutically active substance at high
concentration even when each was produced on the scale of about 125
g, and exhibited an extremely high suppressed effect on the initial
excessive release of the physiologically active substance. Any of
these microcapsules accomplished a sustained release of the
physiologically active substance at a constant rate over an
extremely prolonged period.
INDUSTRIAL APPLICABILITY
[0185] An inventive sustained release composition contains a
pharmacologically active substance at a high concentration and
suppresses the initial excessive release of this substance, and
maintains a stable releasing rate for a prolonged period
(preferably about 6 months or longer).
* * * * *