U.S. patent application number 13/564928 was filed with the patent office on 2012-11-22 for sustained-release composition and process for producing the same.
This patent application is currently assigned to Takeda Pharmaceutical Company Limited. Invention is credited to Yoshio HATA, Akiko YAMADA, Kazumichi Yamamoto.
Application Number | 20120295848 13/564928 |
Document ID | / |
Family ID | 26617908 |
Filed Date | 2012-11-22 |
United States Patent
Application |
20120295848 |
Kind Code |
A1 |
Yamamoto; Kazumichi ; et
al. |
November 22, 2012 |
SUSTAINED-RELEASE COMPOSITION AND PROCESS FOR PRODUCING THE
SAME
Abstract
Present invention is to provide a sustained-release composition
which contains a physiologically active substance in high content
even when gelatin is not included, and suppresses its initial
excessive release and, thus, can achieve a stable release rate over
about one month. A sustained-release composition containing a
lactic acid-glycolic acid polymer having a ratio or weight average
molecular weight and number average molecular weight of about 1.90
or lower, or a salt thereof, and a physiologically active
substance.
Inventors: |
Yamamoto; Kazumichi;
(Kyoto-shi, JP) ; YAMADA; Akiko; (Kyoto-shi,
JP) ; HATA; Yoshio; (Kayabe-gun, Hokkaido,
JP) |
Assignee: |
Takeda Pharmaceutical Company
Limited
|
Family ID: |
26617908 |
Appl. No.: |
13/564928 |
Filed: |
August 2, 2012 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11960114 |
Dec 19, 2007 |
8258252 |
|
|
13564928 |
|
|
|
|
10479516 |
Dec 10, 2003 |
|
|
|
PCT/JP02/06526 |
Jun 28, 2002 |
|
|
|
11960114 |
|
|
|
|
Current U.S.
Class: |
514/10.3 ;
514/1.1; 514/772.3; 514/9.7; 528/361 |
Current CPC
Class: |
A61P 13/08 20180101;
A61P 5/24 20180101; A61P 15/18 20180101; A61P 15/08 20180101; A61K
9/1647 20130101; A61P 37/02 20180101; A61P 35/00 20180101; A61P
5/06 20180101; A61P 5/00 20180101; A61K 38/09 20130101; A61P 15/00
20180101; A61P 25/28 20180101 |
Class at
Publication: |
514/10.3 ;
514/772.3; 514/1.1; 514/9.7; 528/361 |
International
Class: |
A61K 47/34 20060101
A61K047/34; A61K 38/09 20060101 A61K038/09; C08G 63/08 20060101
C08G063/08; A61P 13/08 20060101 A61P013/08; A61P 15/00 20060101
A61P015/00; A61P 15/18 20060101 A61P015/18; A61K 38/02 20060101
A61K038/02; A61P 35/00 20060101 A61P035/00 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 29, 2001 |
JP |
2001-199462 |
Nov 6, 2001 |
JP |
2001-340980 |
Claims
1. A sustained-release composition containing a lactic
acid-glycolic acid polymer having a ratio of weight average
molecular weight to number average molecular weight of about 1.90
or lower, or a salt thereof, and a physiologically active
substance.
2. The sustained-release composition according to claim 1, wherein
the physiologically active substance is a physiologically active
peptide.
3. The sustained-release composition according to claim 2, wherein
the physiologically active substance is an LH-RH derivative.
4. The sustained-release composition according to claim 1, wherein
weight average molecular weight of said lactic acid-glycolic acid
polymer is about 3,000 to about 100,000.
5. The sustained-release composition according to claim 4, wherein
weight average molecular weight of lactic acid-glycolic acid
polymer is about 8,000 to about 15,000.
6. The sustained-release composition according to claim 1, wherein
the ratio of the low molecular weight fraction of molecular weight
of lactic acid-glycolic acid polymer of about 3,000 or smaller is
about 9% or lower.
7. The sustained-release composition according to claim 6, wherein
the ratio of the low molecular weight fraction of molecular weight
of lactic acid-glycolic acid polymer of about 3,000 or smaller is
about 3% to about 9%.
8. The sustained-release composition according to claim 1, wherein
said polymer has a molar ratio of lactic acid to glycolic acid of
from 100:0 to 40:60.
9. The sustained-release composition according to claim 1, wherein
said polymer has a molar ratio of lactic acid to glycolic acid of
from 70:30 to 80:20.
10. The sustained-release composition according to claim 3, wherein
the LH-RH derivative is a peptide represented by the 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
HN-C.sub.2H.sub.5 or Gly-NH.sub.2, or a salt thereof.
11. The sustained-release composition according to claim 3, wherein
the LH-RH derivative is a peptide represented by the formula:
5-oxo-Pro-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH-C.sub.2H.sub.5, or
acetate thereof.
12. The sustained-release composition according to claim 3, wherein
the LH-RH derivative or a salt thereof is contained at about 5%
(w/w) to about 24% (w/w) in the sustained-release composition.
13. The sustained-release composition according to claim 1, wherein
the physiologically active substance or a salt thereof is slightly
water-soluble or water-soluble.
14. The sustained-release composition according to claim 1, which
is for injection.
15. The sustained-release composition according to claim 1, which
releases a physiologically active substance or a salt thereof over
at least two weeks.
16. The sustained-release composition according to claim 1, which
does not contain a drug retaining substance.
17. The sustained-release composition according to claim 1, which
does not contain gelatin.
18. A process for producing the sustained-release composition
according to claim 1, which comprises removing a solvent from a
mixed solution containing a physiologically active substance or a
salt thereof and a lactic acid-glycolic acid polymer having a ratio
of weight average molecular weight to number average molecular
weight of about 1.90 or lower, or a salt thereof.
19. The process according to claim 18, which comprises mixing and
dispersing a physiologically active substance or a salt thereof in
an organic solvent solution containing a lactic acid-glycolic acid
polymer having a ratio of weight average molecular weight to number
average molecular weight of about 1.90 or lower or a salt thereof,
and removing the organic solvent.
20. The process according to claim 19, wherein the physiologically
active substance or a salt thereof is used as an aqueous solution
containing the physiologically active substance or a salt
thereof.
21. A pharmaceutical comprising the sustained-release composition
according to claim 1.
22. A method for preventing or treating prostate cancer,
prostatomegaly, endometriosis, hysteromyoma, metrofibroma,
precocious puberty and dysmenorrhea, or a contraceptive, which
comprises administering to a mammal an effective dose of the
sustained-release composition according to claim 3.
23. A method for preventing recurrence of breast cancer after the
operation for premenopausal breast cancer, which comprises
administering to a mammal an effective dose of the
sustained-release composition according to claim 3.
24. A lactic acid-glycolic acid polymer having weight average
molecular weight of about 8,000 to about 15,000 and having a ratio
of weight average molecular weight to number average molecular
weight of about 1.90 or lower, or a salt thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Continuation of U.S. application Ser.
No. 11/960,114, filed Dec. 19, 2007, which is a Divisional of U.S.
application Ser. No. 10/479,516, which is the U.S. National Stage
of PCT/JP02/06526, filed Jun. 28, 2002, which claims priority to
Japanese Application No. 2001-199462, filed Jun. 29, 2001, and
Japanese Application No. 2001-340980, filed Nov. 6, 2001. The
entire contents of each of the aforementioned applications are
incorporated herein by reference.
TECHNICAL FIELD
[0002] The present invention relates to a sustained-release
preparation of a physiologically active substance and a process for
producing the same.
BACKGROUND ART
[0003] In JP-A 60-100516, a sustained-release microcapsule of a
water-soluble drug, which comprises a particle of an average
diameter of 2 to 200 .mu.m containing a water-soluble drug
dispersed in a matrix comprising a lactic acid-glycolic acid
copolymer having weight average molecular weight of about 5000 to
200000 and comprising about 100 to 50% by weight of lactic acid and
about 0 to 50% by weight of glycolic acid, and which is prepared by
a method of drying in water is disclosed.
[0004] In JP-A 62-201816, a sustained-release microcapsule
characterized in that the viscosity of a W/O type emulsion upon
preparation of a W/O/W type emulsion is adjusted to about 150 to
10000 cp, and a process for preparing the same are disclosed.
[0005] In JP-A 62-54760, there are disclosed a biodegradable
polyoxycarboxylic ester which is a copolymer or a polymer having
the content of water-soluble oxycarboxylic acid of less than 0.01
mole/100 g in terms of a monobasic acid and having a weight average
molecular weight of about 2000 to 50000, and an injection
sustained-release microcapsule containing the polymer.
[0006] In JP-A 61-28521, there are disclosed a lactic acid-glycolic
acid copolymer which has weight average molecular weight of about
5000 to 30000, does not contain a catalyst, has the dispersibility
(by a gel permeation chromatography method) of about 1.5 to 2 and
comprises about 50 to 95% by weight of lactic acid and 50 to 5% by
weight of glycolic acid, and a pharmaceutical containing the
polymer as a base.
[0007] In JP-A 6-192068, there is disclosed a process for preparing
a sustained-release microcapsule, which comprises heating a
microcapsule at a temperature higher than the glass transition
temperature of a polymer, at which respective particles of the
microcapsule do not adhere to each other.
[0008] In JP-A 4-218528, there is disclosed a method for purifying
biodegradable aliphatic polyester, which comprises dissolving a
biodegradable aliphatic polyester containing a low-molecular weight
polymer having a molecular weight of 1,000 or smaller in an organic
solvent, adding water thereto to precipitate a polymeric substance,
and removing low-molecular weight polymer having molecular weight
of 1,000, and there is described that water is added at 50 to 150
(ratio by volume) relative to 100 of the organic solvent.
OBJECTS OF THE INVENTION
[0009] The present invention is to provide a sustained-release
preparation which does not contain gelatin and contains a
physiologically active substance in a large amount, and which can
achieve a stable release rate over about one month by suppressing
any initial excessive release of physiologically active
substance.
SUMMARY OF THE INVENTION
[0010] In order to solve the aforementioned problem, the present
inventors studied intensively and, as a result, found a
sustained-release preparation which contains a physiologically
active substance in a large amount without containing gelatin and
which can suppress any initial excessive release of physiologically
active substance to achieve a stable release rate over about one
month, by preparing a polymer having a ratio of weight average
molecular weight to number average molecular weight of PLGA as a
base about 1.90 or lower, or by using a lactic acid-glycolic acid
polymer having weight average molecular weight of about 11,600 to
about 140,000 or a salt thereof, which resulted in completion of
the present invention.
[0011] That is, the present invention provides:
(1) A sustained-release composition containing a lactic
acid-glycolic acid polymer having a ratio of weight average
molecular weight to number average molecular weight of about 1.90
or lower, or a salt thereof, and a physiologically active
substance, (2) the sustained-release composition described in the
(1), wherein the physiologically active substance is a
physiologically active peptide, (3) the sustained-release
composition described in the (2), wherein the physiologically
active substance is an LH-RH derivative, (4) the sustained-release
composition described in the (1), wherein weight average molecular
weight of a lactic acid-glycolic acid polymer is about 3,000 to
about 100,000, (5) the sustained-release composition described in
the (4), wherein weight average molecular weight of a lactic
acid-glycolic acid polymer is about 8,000 to about 15,000, (6) the
sustained-release composition described in the (1), wherein the
ratio of the low molecular weight fraction of molecular weight of
lactic acid-glycolic acid polymer of about 3,000 or smaller is
about 9% or lower, (7) the sustained-release composition described
in the (6), wherein the ratio of the low molecular weight fraction
of molecular weight of lactic acid-glycolic acid polymer of about
3,000 or smaller is about 3% to about 9%, (8) the sustained-release
composition described in the (1), wherein said polymer has a molar
ratio of lactic acid to glycolic acid of from 100:0 to 40:60, (9)
the sustained-release composition described in the (1), wherein
said polymer has a molar ratio of lactic acid to glycolic acid of
from 70:30 to 80:20, (10) the sustained-release composition
described in the (3), wherein the LH-RH derivative is a peptide
represented by the 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 HN-C.sub.2H.sub.5 or Gly-NH.sub.2, or a
salt thereof, (11) the sustained-release composition described in
the (3), wherein the LH-RH derivative is a peptide represented by
the formula:
5-oxo-Pro-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH-C.sub.2H.sub.5,
or acetate thereof, (12) the sustained-release composition
described in the (3), wherein the LH-RH derivative or a salt
thereof is contained at about 5% (w/w) to about 24% (w/w) in the
sustained-release composition, (13) the sustained-release
composition described in the (1), wherein the physiologically
active substance or a salt thereof is slightly water-soluble or
water-soluble, (14) the sustained-release composition described in
the (1), which is for injection, (15) the sustained-release
composition described in the (1), which releases a physiologically
active substance or a salt thereof over at least two weeks, (16)
the sustained-release composition described in the (1), which does
not contain a drug retaining substance, (17) the sustained-release
composition described in the (1), which does not contain gelatin,
(18) a process for producing the sustained-release composition as
defined in the (1), which comprises removing a solvent from a mixed
solution containing a physiologically active substance or a salt
thereof and a lactic acid-glycolic acid polymer having a ratio of
weight average molecular weight to number average molecular weight
of about 1.90 or lower, or a salt thereof, (19) the process
described in the (18), which comprises mixing and dispersing a
physiologically active substance or a salt thereof in a solution,
in an organic solvent, containing a lactic acid-glycolic acid
polymer having a ratio of weight average molecular weight to number
average molecular weight of about 1.90 or lower, or a salt thereof,
and removing the organic solvent, (20) the process described in the
(19), wherein the physiologically active substance or a salt
thereof is used as an aqueous solution containing the
physiologically active substance or a salt thereof, (21) a
pharmaceutical comprising the sustained-release composition as
defined in the (1), (22) an agent for preventing or treating
prostate cancer, prostatomegaly, endometriosis, hysteromyoma,
metrofibroma, precocious puberty, dysmenorrhea and breast cancer,
or a contraceptive, which comprises the sustained-release
composition as defined in the (3), (23) an agent for preventing
recurrence of breast cancer after the operation for premenopausal
breast cancer, which comprises the sustained-release composition as
defined in the (3), (24) a method for preventing or treating
prostate cancer, prostatomegaly, endometriosis, hysteromyoma,
metrofibroma, precocious puberty and dysmenorrhea, or a
contraceptive, which comprises administering to a mammal an
effective dose of the sustained-release composition as defined in
the (3), (25) a method for preventing recurrence of breast cancer
after the operation for premenopausal breast cancer, which
comprises administering to a mammal an effective dose of the
sustained-release composition as defined in the (3), (26) a process
for producing a lactic acid-glycolic acid polymer having a weight
average molecular weight of about 8,000 to about 15,000 and having
a ratio of weight average molecular weight to number average
molecular weight of about 1.90 or lower, or a salt thereof, which
comprises adding water to an organic solvent containing a lactic
acid-glycolic acid polymer having weight average molecular weight
of about 5,000 to about 15,000 at a ratio of less than about 5 to
50 (ratio by volume) relative to 100 of the organic solvent, (27)
the process for producing a polymer described in the (26), wherein
the organic solvent is hydrophilic, (28) the process for producing
a polymer described in the (27), wherein the hydrophilic organic
solvent is acetone, (29) the process for producing a polymer
described in the (26), wherein the ratio of water relative to 100
of the organic solvent is about 10 to about 45 (ratio by volume),
(30) the process for producing a polymer described in the (26),
wherein the ratio of water relative to 100 of the organic solvent
is about 40 (ratio by volume), (31) a lactic acid-glycolic acid
polymer having weight average molecular weight of about 8,000 to
about 15,000 and having a ratio of weight average molecular weight
to number average molecular weight of about 1.90 or lower, or a
salt thereof, (32) use of lactic acid-glycolic acid polymer or salt
thereof described in the (31) for producing the sustained-release
composition which does not include gelatin, (33) a microsphere
containing a lactic acid-glycolic acid polymer having weight
average molecular weight of about 11,600 to about 14,000 or a salt
thereof, and a LH-RH derivative or a salt thereof, and not
containing gelatin, (34) the microsphere described in the (33),
wherein the LH-RH derivative or a salt thereof is a peptide
represented by the 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 HH, C.sub.2H.sub.5 or Gly-NH.sub.2, or a
salt thereof, (35) the microsphere described in the (33), wherein
the LH-RH derivative or a salt thereof is a peptide represented by
the formula:
5-oxo-Pro-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH-C.sub.2H.sub.5,
or acetate thereof, (36) the microsphere described in the (33),
wherein the LH-RH derivative or a salt thereof is contained at
about 5% (w/w) to about 24% (w/w), (37) the microsphere described
in the (33), which is a microcapsule, (38) the microsphere
described in the (33), wherein the LH-RH derivative or a salt
thereof is released during at least more than 2 weeks, (39) an
agent for preventing or treating prostate cancer, prostatomegaly,
endometriosis, hysteromyoma, metrofibroma, precocious puberty and
dysmenorrhea, or a contraceptive, which comprises the microsphere
described in the (33), (40) an agent for preventing recurrence of
breast cancer after the operation for premenopausal breast cancer,
which comprises the microsphere described in the (33), (41) a
method for preventing or treating prostate cancer, prostatomegaly,
endometriosis, hysteromyoma, metrofibroma, precocious puberty and
dysmenorrhea, or a contraceptive, which comprises administering to
a mammal an effective dose of the microsphere described in the
(33), (42) a method for preventing recurrence of breast cancer
after the operation for premenopausal breast cancer, which
comprises administering to a mammal an effective dose of the
microsphere described in the (33).
DETAILED DESCRIPTION OF THE INVENTION
[0012] The physiologically active substance used in the present
invention is not particularly limited as long as it is
pharmaceutically useful, and a non-peptide compound or peptide
compound. Examples of a suitable non-peptide compound include an
agonist, an antagonist, and a compound having the enzyme inhibiting
activity. In addition, as the peptide compound, for example, a
physiologically active peptide is preferable. Physiologically
active peptides having a molecular weight of about 3000 to about
40,000, preferably about 4000 to about 30,000, more preferably
about 5000 to about 200,000 are suitable.
[0013] Examples of the physiologically active peptide include
luteinizing hormone-releasing hormone (LH-RH), insulin,
somatostatin, somatotropin, growth hormone-releasing hormone
(GH-RH), prolactin, erythropoietin, adrenal cortical hormone,
melanocyte-stimulating hormone, thyroid hormone-releasing hormone,
thyroid-stimulating hormone, luteinizing hormone,
follicle-stimulating hormone, vasopressin, oxytocin, calcitonin,
gastrin, secretin, pancreozymin, cholecystokinin, angiotensin,
human placental lactogen, human chorionic gonadotropin, enkephalin,
endorphin, kyotrophin, tuftsin, thymopoietin, thymosin,
thymotimurin, thymus humoran factor, blood thymus factor, tumor
necrosis factor, colony-inducing factor, motilin, dynorphin,
bombesin, neurotensin, cerulein, bradykinin, atrial natriuretic
excretion-increasing factor, nerve growth factor, cell growth
stimulator, neurotrophic factor, peptides having the endothelin
antagonistic activity and derivatives, fragments thereof and
derivatives of the fragments.
[0014] The physiologically active substance used in the present
invention may be itself or maybe a pharmacologically salt
thereof.
[0015] When the physiologically active substance has a basic group
such as an amino group, examples of such salts include salts with
inorganic acids (also referred to as inorganic free acid) (for
example, carbonic acid, bicarbonic acid, hydrochloric acid,
sulfuric acid, nitric acid, boric acid and the like), and organic
acids (also referred to as organic free acid) (for example,
succinic acid, acetic acid, propionic acid, trifluoroacetic acid
and the like), when the physiologically active substance has an
acidic group such as a carboxyl group and the like, examples of
such the salt include salts with inorganic base (also referred to
as inorganic free base) (for example, alkali metal such as sodium,
potassium and the like, alkaline earth metal such as calcium,
magnesium and the like), and organic bases (also referred to as
organic free base) (for example, organic amines such as
triethylamine and the like, basic amino acids such as arginine and
the like). In addition, the physiologically active peptide may form
a metal complex compound (for example, copper complex, zinc complex
and the like).
[0016] Preferable examples of the physiologically active peptide
include LH-RH derivatives or salts thereof which are effective for
hormone dependent diseases, in particular, sex hormone dependent
cancers (for example, prostate cancer, uterine cancer, breast
cancer, pituitary gland tumor and the like), sex hormone dependent
disease such as prostatomegaly, endometriosis, hysteromyoma,
precocious puberty, dysmenorrhea, amenorrhea, premenstrual
syndrome, multilocular ovary syndrome and the like, contraception
(or, when the rebound activity after cease of administration is
utilized, infertility), prevention of recurrence of breast cancer
after the operation for premenopausal breast cancer. Further,
examples include LH-RH derivatives or salts thereof effective for
benign or malignant tumors which are sex hormone independent but
LH-RH sensitive.
[0017] Specific examples of the LH-RH derivatives or salts thereof
include peptides described in Treatment with GnRH analogs:
Controversies and perspectives (The parthenon Publishing Group
Ltd.) published in 1996, JP-A 3-503165, JP-A 3-101695, JP-A 7-97334
and JP-A 8-259460.
[0018] Examples of the LH-RH derivatives include LH-RH agonists and
LH-RH antagonists. As the LH-RH antagonists, for example, a
physiologically active peptide represented by the general formula
[I]:
X-D2Nal-D4ClPhe-D3Pal-Ser-A-B-Leu-C-Pro-DAlaNH.sub.2
[wherein X denotes N(4H.sub.2-furoyl)Gly or NAc, A denotes a
residue selected from NHeTyr, Tyr, Aph(Atz), and NMeAph(Atz), B
denotes a residue selected from DLys(Nic), DCit, DLis(AzaglyNic),
DLis(AzaglyFur) DhArg(Et.sub.2), DAph(Atz) and DhCi, and C denotes
Lys(Nisp), Arg or hArg(Et.sub.2)], and a salt thereof are used.
[0019] As the LH-RH agonist, for example, a physiologically active
peptide represented by the general 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), D2Nal and DHis(ImBzl), and Z denotes NH-C.sub.2H.sub.5
or Gly-NH.sub.2] or a salt thereof is used. In particular, a
peptide wherein Y is DLeu and Z is NH-C.sub.2H.sub.5 (that is,
Peptide A represented by
5-oxo-Pro-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH-C.sub.2H.sub.5;
Leuprorelin) or a salt thereof (for example, acetate) is
suitable.
[0020] These peptides can be prepared by the methods described in
the aforementioned publications or patent publications or similar
methods.
[0021] Abbreviations used in the present specification have the
following meanings:
TABLE-US-00001 Abbreviation Name N(4H.sub.2-
N-tetrahydrofuroylglycine residue furoyl)Gly: NAc N-acetyl group
N2Nal 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
[0022] Regarding other acids, abbreviation is expressed based on
abbreviations according to IUPAC-IUB Commission on Biochemical
Nomenclature (European Journal of Biochemistry, Vol. 138, pp 9-37
(1984)) or the conventional abbreviations in the art. In addition,
when an amino acid can have an optical isomer, it denotes L-amino
acid unless indicated otherwise.
[0023] As a lactic acid-glycolic acid polymer used in the present
invention, a lactic acid-glycolic acid polymer having a ratio of
weight average molecular weight of the lactic acid-glycolic acid
polymer to number average molecular weight of the lactic
acid-glycolic acid polymer of about 1.90 or lower is preferably
used.
[0024] A lactic acid-glycolic acid copolymer may be a salt.
Examples of the salt include salts with inorganic bases (for
example, alkali metal such as sodium, potassium and the like, and
alkaline earth metal such as calcium, magnesium and the like) or
organic bases (for example, organic amines such as triethylamine
and the like, and basic amino acids such as arginine and the like),
salts with transition metals (for example, zinc, iron, copper and
the like), and complex salts.
[0025] A constitutional molar ratio of the lactic acid-glycolic
acid polymer is preferably about 100/0 to about 40/60, more
preferably about 70/30 to about 80/20.
[0026] A optical isomer ratio of lactic acid which is one of
minimum repeating units of the "lactic acid-glycolic acid polymer"
is preferably in a range of D-isomer/L-isomer (mole/mole %) of
about 75/25 to about 25/75. In particular, the D-isomer/L-isomer
(mole/mole %) in a range of about 60/40 to about 30/70 is
frequently used.
[0027] A weight average molecular weight of the "lactic
acid-glycolic acid polymer" is usually about 3,000 to about
100,000, preferably about 3,000 to about 50,000, particularly
preferably about 8,000 to about 15,000.
[0028] A ratio of a low molecular weight fraction, having molecular
weight of about 3,000 or smaller, of the "lactic acid-glycolic acid
polymer" is preferably about 9% or lower, more preferably about 3%
to 9% or lower.
[0029] In addition, a lactic acid-glycolic acid polymer in the
present invention has a ratio of weight average molecular weight of
the lactic acid-glycolic acid polymer to number average molecular
weight of the lactic acid-glycolic acid polymer of about 1.90 or
lower, preferably about 1.40 to about 1.90, more preferably about
1.45 to about 1.80.
[0030] Further, preferable examples include:
(1) a lactic acid-glycolic acid polymer having a weight average
molecular weight of about 3,000 to 100,000 and having a ratio of
weight average molecular weight of a lactic acid-glycolic acid
polymer to number average molecular weight of a lactic
acid-glycolic acid polymer of about 1.90 or lower, (2) a lactic
acid-glycolic acid polymer having a weight average molecular weight
of about 3,000 to 50,000 and having a ratio of weight average
molecular weight of a lactic acid-glycolic acid polymer to number
average molecular weight of a lactic acid-glycolic acid polymer of
about 1.90 or lower, (3) a lactic acid-glycolic acid polymer having
a weight average molecular weight of about 8,000 to 15,000 and
having a ratio of weight average molecular weight of a lactic
acid-glycolic acid polymer to number average molecular weight of a
lactic acid-glycolic acid polymer of about 1.90 or lower, (4) a
sustained-release composition described in the (1) to (3), wherein
a ratio of a low molecular weight fraction, having molecular weight
of about 3,000 or smaller, of a lactic acid-glycolic acid polymer
is about 9% or lower, and (5) a sustained-release composition
described in the (1) to (3), wherein a ratio of a low molecular
weight fraction, having molecular weight of about 3,000 or smaller,
of a lactic acid-glycolic acid polymer is about 3% to about 9%.
[0031] More preferable examples include:
(6) a lactic acid-glycolic acid polymer having weight average
molecular weight of about 3,000 to 100,000 and having a ratio of
weight average molecular weight of a lactic acid-glycolic acid
polymer to number average molecular weight of a lactic
acid-glycolic acid polymer of about 1.40 to about 1.90, (7) a
lactic acid-glycolic acid polymer having a weight average molecular
weight of about 3,000 to 50,000 and having a ratio of weight
average molecular weight of a lactic acid-glycolic acid polymer to
number average molecular weight of a lactic acid-glycolic acid
polymer of about 1.40 to about 1.90, (8) a lactic acid-glycolic
acid polymer having weight average molecular weight of about 8,000
to 15,000 and having a ratio of weight average molecular weight of
a lactic acid-glycolic acid polymer to number average molecular
weight of a lactic acid-glycolic acid polymer of about 1.40 to
about 1.90, (9) a sustained-release composition described in the
(6) to (8), wherein a ratio of a low molecular weight fraction,
having molecular weight of about 3,000 or smaller, of a lactic
acid-glycolic acid polymer is about 9% or lower, and (10) a
sustained-release composition described in the (6) to (8), wherein
a ratio of a low molecular weight fraction, having molecular weight
of about 3,000 or smaller, of a lactic acid-glycolic acid polymer
is about 3% to about 9%.
[0032] Most preferable examples include:
(11) a lactic acid-glycolic acid polymer having weight average
molecular weight of about 3,000 to 100,000 and having a ratio of
weight average molecular weight of a lactic acid-glycolic acid
polymer to number average molecular weight of a lactic
acid-glycolic acid polymer of about 1.45 to about 1.80, (12) a
lactic acid-glycolic acid polymer having weight average molecular
weight of about 3,000 to 50,000 and having a ratio of weight
average molecular weight of a lactic acid-glycolic acid polymer to
number average molecular weight of a lactic acid-glycolic acid
polymer of about 1.45 to about 1.80, (13) a lactic acid-glycolic
acid polymer having weight average molecular weight of about 3,000
to 15,000 and having a ratio of weight average molecular weight of
a lactic acid-glycolic acid polymer to number average molecular
weight of a lactic acid-glycolic acid polymer of about 1.45 to
about 1.80, (14) a sustained-release composition described in the
(11) to (13), wherein a ratio of a low molecular weight fraction,
having molecular weight of about 3,000 or smaller, of a lactic
acid-glycolic acid polymer is about 9% or lower, and (15) a
sustained-release composition described in the (11) to (13),
wherein a ratio of a low molecular weight fraction, having
molecular weight of about 3,000 or smaller, of a lactic
acid-glycolic acid polymer is about 3% to about 9%.
[0033] Furthermore, a lactic acid-glycolic acid polymer having
weight average molecular weight of about 11,600 to about 14,000 or
a salt thereof may be used.
[0034] Weight average molecular weight and number average molecular
weight in the present specification refer to molecular weight in
terms of polystyrene measured by gel permeation chromatography
(GPC) using as a standard substance ten kinds of monodisperse
polystyrene having (GPC1) weight average molecular weight of
397000, 189000, 98900, 37200, 17100, 9490, 5870, 2500, 1050 and
495.
[0035] Further, the amount of a low molecular weight fraction of
the polymer having a molecular weight of about 3,000 or smaller
denotes the amount of a fraction having a molecular weight of about
3,000 or smaller within a weight average molecular weight
distribution pattern obtained in the aforementioned GPC
measurement. More specifically, the amount of the area under the
curve of a part corresponding to a molecular weight of about 3,000
or smaller relative to the area under the curve of the calculated
weight average molecular weight distribution pattern is calculated.
Measurement is performed by using a series of high speed GPC
apparatus (manufactured by Toso, HLC-8120GPC, a detection method is
by differential refractive index), TSKguardcolumn Super H-L(4.6
mmi.d..times.35 mm), TSKgel SuperH4000 (6 mmi.d..times.150
mm).times.2, and TSKgel SuperH2000 (6 mmi.d..times.150 mm) (All
columns are manufactured by Toso) and THF as a mobile phase at a
flow rate of 0.6 ml/min.
[0036] When the reaction between a lactic acid-glycolic acid
polymer and a physiologically active substance is an ionic
interaction, the main interaction is between the physiologically
active substance and terminal carboxylic acid of a lactic
acid-glycolic acid polymer. When the low molecular weight fraction
is contained in a large amount, a physiologically active substance
readily interacts with a lactic acid-glycolic acid polymer of a low
molecular weight having high reactivity. In a sustained-release
injection agent, a physiologically active substance involved in
leakage upon preparation and initial release is mainly a
physiologically active substance interacted with this lactic
acid-glycolic acid polymer of a low molecular weight fraction. In
order to increase the content of the physiologically active
substance and suppress the amount of its initial release, it is
necessary that a ratio of this lactic acid-glycolic acid polymer of
a low molecular weight fraction is reduced below a certain level,
and the ratio of weight average molecular weight to number average
molecular weight is reduced below a certain level. For this reason,
for example, in order to obtain a lactic acid-glycolic acid polymer
for an one month-type sustained release preparation, a lactic
acid-glycolic acid polymer is preferable, such a lactic
acid-glycolic acid is preferable that the aforementioned weight
average molecular weight is about 8,000 to about 15,000, a ratio of
weight average molecular weight to number average molecular weight
is about 1.90 or lower, preferably about 1.40 to about 1.90, more
preferably about 1.45 to about 1.80, and the amount of a low
molecular weight fraction having a weight average molecular weight
of 3,000 or smaller is about 9% or lower, preferably about 3% to
about 9%.
[0037] The "lactic acid-glycolic acid polymer" can be prepared by
dehydration polycondensation without a catalyst from lactic acid
and glycolic acid (JP-A 61-28521) or ring-opening polymerization
from lactide and a cyclic diester compound such as glycolide and
the like (Encyclopedic Handbook of Biomaterials and Bioengineering
Part A: Materials, Volume 2, Marcel Dekker, Inc, 1995).
[0038] A lactic acid-glycolic acid polymer obtained by dehydration
polycondensation without a catalyst from lactic acid and glycolic
acid generally has a large amount of low molecular weight fraction,
and has a ratio of weight average molecular weight to number
average molecular weight of about 2 or higher. The weight average
molecular weight of a lactic acid-glycolic acid copolymer used in
the present specification is about 5,000 to about 15,000. The
amount of the low molecular weight fraction having a molecular
weight of about 3,000 or smaller can vary depending on weight
average molecular weight and, when weight average molecular weight
is about 10,000, the amount of low molecular weight fraction having
molecular weight of about 3,000 or smaller is about 10% or
higher.
[0039] The resulting lactic acid-glycolic acid polymer can be
purified by using an organic solvent to obtain an end polymer.
[0040] Examples of an organic solvent used in the present invention
include preferably a hydrophilic or a readily water-soluble organic
solvent such as, for example, acetone, tetrahydrofuran, dioxane,
dimethylformamide and dimethyl sulfoxide and, inter alia, acetone
is preferably used.
[0041] The amount of water and organic solvent used in the present
invention to be added is not particularly limited. However, when
the amount of water is too large, reduction of the low molecular
weight fraction is insufficient and, thus, it is difficult to
obtain an end polymer. On the other hand, when the amount of water
is too small, the polymer becomes difficult to precipitate and,
therefore, recovery is deteriorated and only a polymer having a
higher molecular weight than the desired molecular weight is
recovered. Usually, the amount of water relative to 100 of an
organic solvent is about 5 to 50, preferably about 10 to about 45,
more preferably about 24 to about 40, particularly preferably about
40. For example, 10 g of a lactic acid-glycolic acid polymer is
dissolved in 100 mL of acetone which is an organic solvent, 40 mL
of purified water is gradually added thereto while stirring by a
suitable method, to precipitate an end polymer, which can be dried
by a suitable method. When an end polymer can not be obtained by a
single dissolution and precipitation step, this procedure may be
repeated.
[0042] In the sustained-release preparation of the present
invention, a base is preferably a lactic acid-glycolic acid polymer
having a ratio of weight average molecular weight to number average
molecular weight of about 1.90 or lower, or a salt thereof, or a
lactic acid-glycolic acid polymer having weight average molecular
weight of about 11,600 to about 14,000 or a salt thereof. A
constitutional molar ratio of lactic acid and glycolic acid is
preferably 100/0 to 40/60. A physiologically active substance is
preferably a LH-RH derivative and particularly preferably a LH-RH
derivative is the peptide represented by the formula:
5-oxo-Pro-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH-C.sub.2H.sub.5
or acetate thereof. The content of a LH-RH derivative or a salt
thereof is preferably about 5% (w/w) to about 24% (w/w). Further,
preferable is such a sustained-release preparation that does not
contain gelatin and releases a physiologically active substance or
a salt thereof over at least two weeks.
A Method of Preparing a Microcapsule
[0043] The thus obtained lactic acid-glycolic acid polymer can be
used as a base for preparing a sustained-release preparation. A
method of preparing a sustained-release composition, for example, a
microcapsule containing a physiologically active substance or a
salt thereof, and a lactic acid-glycolic acid polymer or a salt
thereof of the present invention is exemplified.
(I) A Method of Drying in Water
(i) O/W Method
[0044] In the present method, first, a solution of a lactic
acid-glycolic acid polymer or a salt thereof in an organic solvent
is prepared. It is preferable that an organic solvent used for
preparing a sustained-release preparation of the present invention
has a boiling point of 120.degree. C. or lower.
[0045] As the organic solvent, for example, halogenated hydrocarbon
(for example, dichloromethane, chloroform, dichloroethane,
trichloroethane, carbon tetrachloride and the like), ethers (for
example, ethyl ether, isopropyl ether and the like), fatty acid
ester (for example, ethyl acetate, butyl acetate and the like),
aromatic hydrocarbon (for example, benzene, toluene, xylene and the
like), alcohols (for example, ethanol, methanol and the like), and
acetonitrile are used, and a solvent of the mixture of them is
used. As an organic solvent for a lactic acid-glycolic acid polymer
or a salt thereof, inter alia, dichloromethane is preferable.
[0046] The concentration of lactic acid-glycolic acid polymer in
solution in an organic solvent can vary depending on the molecular
weight of a lactic acid-glycolic acid polymer and the type of
organic solvent. For example, when dichloromethane is used as an
organic solvent, the concentration is selected generally from about
0.5 to about 70% by weight, more preferably about 1 to about 60% by
weight, particularly preferably about 2 to about 50% by weight.
[0047] A physiologically active substance or a salt thereof is
added to, and dissolved or dispersed in the thus obtained solution
of a lactic acid-glycolic acid polymer in an organic solvent. Then,
the resulting solution in an organic solvent containing a
composition comprising a physiologically active substance or a salt
thereof and a lactic acid-glycolic acid polymer or a salt thereof
is added to an aqueous phase to form an 0 (oily phase)/W (aqueous
phase) emulsion, a solvent in an oily phase is volatilized or
diffused in an aqueous phase to prepare a microcapsule. Upon this,
a volume of an aqueous phase is selected generally from about 1 to
about 10,000-fold, more preferably about 5 to 50,000-fold,
particularly preferably about 10 to 2,000-fold an oily phase
volume.
[0048] An emulsifier may be added to an aqueous phase besides the
aforementioned components. Any emulsifier may be used as long as it
can generally form a stable O/W emulsion. Specifically, for
example, anionic surfactants (sodium oleate, sodium stearate,
sodium laurylsulfate and the like), nonionic surfactants
(polyoxyethylene sorbitan fatty acid esters (Tween 80, Tween 60,
manufactured by Atlas Powder), polyoxyethylene castor oil
derivative (HCO-60, HCO-50, manufactured by Nikko Chemical),
polyvinyl pyrrolidone, polyvinyl alcohol, carboxymethylcellulose,
lecithin, gelatin and hyaluronic acid are used. These may be used
alone or in combination of some of them. The concentration upon use
is preferably in a range of about 0.0001 to 10% by weight, more
preferably in a range of about 0.001 to 5% by weight.
[0049] An osmotic pressure regulating agent may be added to an
aqueous phase besides the aforementioned components. Any osmotic
pressure regulating agent may be used as long as it produces
osmotic pressure when formulated into an aqueous solution.
[0050] Examples of the osmotic pressure regulating agent include
polyhydric alcohols, monohydric alcohols, monosaccharides,
disaccharides, oligosaccharide and amino acids or derivatives
thereof.
[0051] As the polyhydric alcohols, for example, trihydric alcohols
such as glycerin and the like, pentahydric alcohols such as
arabitol, xylitol, adonitol and the like, and hexahydric alcohols
such as mannitol, sorbitol, dulcitol and the like are used. Inter
alia, hexahydric alcohols are preferable, in particular, mannitol
is suitable.
[0052] Examples of the monohydric alcohols include methanol,
ethanol and isopropyl alcohol and, inter alia, ethanol is
preferable.
[0053] As the monosaccharides, for example, pentoses such as
arabinose, xylose, ribose, 2-deoxyribose and the like, and hexoses
such as glucose, fructose, galactose, mannose, sorbose, rhamnose,
fucose and the like are used and, among them, hexoses are
preferable.
[0054] As the oligosaccharides, for example, trisaccharides such as
maltotriose, raffinose and the like, and tetrasaccharides such as
stachyose and the like are used and, among them, trisaccharides are
preferable.
[0055] As the derivatives of monosaccharides, disaccharides and
oligosaccharide, for example, glucosamine, galactosamine,
glucuronic acid and galacturonic acid are used.
[0056] As the amino acids, any L-amino acids can be used and
examples thereof include glycine, leucine and arginine. Among them,
L-arginine is preferable.
[0057] These osmotic regulating agents may be used alone or in
combination.
[0058] These osmotic regulating agents are used at the
concentration such that osmotic pressure of an external aqueous
phase is about 1/50 to about 5-fold, preferably about 1/25 to about
3-fold osmotic pressure of a physiological saline solution. When
mannitol is used as an osmotic pressure regulating agent, its
concentration is preferably 0.5% to 1.5%.
[0059] As a method of removing organic solvent, the method known
per se or a similar method is used. Examples of the method include
a method of evaporating an organic solvent at a normal pressure or
by reducing pressure to reduced pressure gradually while stirring
with a propeller type stirrer, a magnetic stirrer or an ultrasound
generating apparatus, a method of evaporating an organic solvent
while the vacuum degree is regulated using a rotary evaporator, and
a method of gradually removing an organic solvent using a dialysis
membrane.
[0060] The thus obtained microcapsule is centrifuged or filtered to
recover a free physiologically active substance or a salt thereof,
a drug retaining substance and an emulsifier which are attached to
the surface of a microcapsule, are washed with distilled water
several times, and dispersed again in distilled water, which is
lyophilized.
[0061] Since a microcapsule of the present invention uses as a base
a lactic acid-glycolic acid polymer having a ratio of weight
average molecular weight to number average molecular weight of 1.90
or lower, or a salt thereof, or a lactic acid-glycolic acid polymer
having weight average molecular weight of about 11,600 to about
14,000 or a salt thereof, the microcapsule can contain a drug in
high content and, thus, it is not necessary that the microcapsule
contains a drug retaining substance such as gelatin and a
thickening agent.
[0062] These polymers can be used preferably for manufacturing a
sustained-release composition which releases a drug over at least
two weeks.
[0063] During the preparation step, an aggregation-preventing agent
may be added in order to prevent aggregation of particles. As the
aggregation-preventing agent, for example, a water soluble
polysaccharide such as mannitol, lactose, glucose and starches (for
example, corn starch and the like), an amino acid such as glycine,
and a protein such as fibrin and collagen are used. Among them,
mannitol is suitable.
[0064] After lyophilization, if necessary, water and an organic
solvent in the microcapsule may be removed by warming within
conditions under which microcapsules are not fused. Preferably,
warming is performed at a temperature around or slightly higher
than an intermediate glass transition temperature of a microcapsule
obtained by a differential scanning calorimeter under the
conditions of a temperature increasing rate of 10 to 20.degree. C.
per min. More preferably, warming is performed at a temperature
around the intermediate glass transition temperature of a
microcapsule or in the temperature range from the intermediate
glass transition temperature of a microcapsule to a temperature
higher by about 30.degree. C. than the intermediate glass
transition temperature thereof. Preferably, warming is performed in
the range of a temperature from around the intermediate glass
transition temperature of a microcapsule to higher by 10.degree. C.
than the intermediate glass transition temperature thereof, more
preferably in the range of a temperature from around the
intermediate glass transition temperature to higher by 5.degree. C.
than the intermediate glass transition temperature.
[0065] Warming time can vary depending on the amount of
microcapsule and is generally about 12 hours to 168 hours,
preferably about 24 hours to 120 hours, particularly preferably
about 48 hours to 96 hours after the temperature of the
microcapsule itself reaches a prescribed temperature.
[0066] The warming method is not particularly limited as long as
the aggregation of microcapsules is uniformly warmed by the
method.
[0067] As a method of warming and drying, for example, a method of
warming and drying in a thermostatic chamber, a fluidizing chamber,
a moving chamber or a kiln, and a method of warming and drying with
a microwave are used. Among them, a method of warming and drying in
a thermostatic chamber is preferable.
(ii) W/O/W Method
[0068] First, a solution of a lactic acid-glycolic acid polymer or
a salt thereof in an organic solvent is prepared, and the thus
obtained organic solvent solution is referred to as an oily phase.
The method of preparation is the same as that described in section
(I)(i) above. The concentration of lactic acid-glycolic acid
polymer in an organic solvent can vary depending on the molecular
weight of lactic acid-glycolic acid polymer and type of organic
solvent and, for example, when dichloromethane is used as an
organic solvent, the concentration is selected from generally about
0.5 to about 70% by weight, more preferably about 1 to about 60% by
weight, particularly preferably about 2 to about 50% by weight.
[0069] Next, a solution or a dispersion of a physiologically active
substance or a salt thereof [the solvent is water or a mixture of
water and alcohols (for example, methanol, ethanol and the like)]
is prepared.
[0070] The concentration of physiologically active substance or a
salt thereof to be added is generally 0.001 mg/ml to 10 g/ml, more
preferably 0.1 mg/ml to 5 g/ml, more preferably 10 mg/ml to 3
g/ml.
[0071] When the above-described physiologically active substance
has a basic group such as amino group, salts of physiologically
active substance include a salt with inorganic acid (also referred
to as inorganic free acid) (for example, carbonic acid, acid
carbonate, hydrochloric acid, sulfuric acid, nitric acid, boric
acid etc.), organic acid (also referred to as organic free acid)
(for example, succinic acid, acetic acid, propionic acid,
trifluoracetic acid etc.).
[0072] When a physiologically active substance has a acidic group
such as carboxyl group, salts of physiologically active substance
include a salt with inorganic base (also referred to as inorganic
free base) (for example, alkali metals such as sodium, potassium,
alkali earth metals such as calcium, magnesium, etc.), organic base
(also referred to as organic free base) (for example, organic
amines such as triethylamine, basic amino acids such as arginine,
etc.). Further, physiologically active peptides may form a metal
complex compound (for example, copper complex, zinc complex etc.).
When a physiologically active substance is a LHRH derivative,
acetic acid is particularly preferably added.
[0073] As a solubilizing agent and a stabilizing agent, known ones
may be used. In order to dissolve or disperse a physiologically
active substance or an additive, heating, shaking and stirring may
be performed to such an extent that the activity is not lost, and
thus obtained aqueous solution is referred to as an inner aqueous
phase.
[0074] The thus obtained inner aqueous phase and oily phase are
emulsified by known methods such as a homogenization and ultrasound
to form a W/O emulsion.
[0075] The volume of oily phase to be mixed is about 1 to about
1000-fold, preferably 2 to 100-fold, more preferably about 3 to
10-fold relative to the volume of the inner aqueous phase.
[0076] The range of the viscosity of the resulting W/O emulsion is
generally about 10 to 10,000 cp, preferably about 100 to 5,000 cp,
particularly preferably about 500 to 2,000 cp at about 12 to
25.degree. C.
[0077] Then the resulting W/O emulsion comprising a physiologically
active substance or a salt thereof and a lactic acid-glycolic acid
polymer or a salt thereof is added to an aqueous phase to form a W
(inner aqueous phase)/O (oily phase)/W (external aqueous phase), a
solvent in an oily phase is volatilized or diffused into an
external aqueous phase to prepare a microcapsule. Upon this, a
volume of an external aqueous phase is selected from generally
about 1-fold to about 10,000-fold, more preferably about 5-fold to
about 50,000-fold, particularly preferably about 10-fold to about
2,000-fold a volume of an oily phase.
[0078] An emulsifier and an osomotic pressure regulating agent
which may be added to the aqueous phase besides the aforementioned
components, and the methods of preparation thereafter are the same
as those described in section (I) (i) above.
(II) Phase Separating Method
[0079] When a microcapsule is prepared by the present method, a
coacervating agent is gradually added to an organic solvent
solution containing a physiologically active substance or a salt
thereof and a lactic acid-glycolic acid polymer or a salt thereof
described in a method of drying in water in the (I) while stirring,
to precipitate and solidify a microcapsule. The volume of the
coacervating agent may be from about 0.01 to 1,000-fold, preferably
about 0.05 to 500-fold, particularly preferably about 0.1 to
200-fold of the volume of the oily phase.
[0080] The coacervating agent is not particularly limited as long
as it is a polymer series, mineral oil series or plant oil series
compound which is compatible with an organic solvent, and does not
dissolve the complex of the physiologically active substance or a
salt thereof and the lactic acid-glycolic acid polymer of a salt
thereof. Specifically, for example, silicone oil, sesame oil,
soybean oil, corn oil, cottonseed oil, coconut oil, linseed oil,
mineral oil, n-hexane or n-heptane may be used. These may be used
by mixing 2 or more of them.
[0081] The thus obtained microcapsule is recovered, washed
repeatedly with heptane or the like to remove the coacervating
agent from the composition comprising a physiologically active
substance or a salt thereof and a lactic acid-glycolic acid polymer
or a salt thereof, which is then dried under reduced pressure.
Alternatively, washing is performed in the same manner as that
described as a method of drying in water in section (I)(i) above,
which is lyophilized and further warmed and dried.
(III) Spraying Drying Method
[0082] When a microcapsule is prepared by the present method, an
organic solvent solution containing a physiologically active
substance or a salt thereof and a lactic acid-glycolic acid polymer
or a salt thereof described in a method of drying in water in
section (I) is sprayed in a drying chamber of a spray dryer using a
nozzle, and an organic solvent in finely-divided droplets is
volatilized in an extremely short time to prepare a microcapsule.
Examples of the nozzle include to fluid nozzle type, pressure
nozzle type, rotation disc type. Thereafter, if necessary, the
microcapsule may be washed, lyophilized and further warmed and
dried by the same method as that described in a method of drying in
water in section (I).
[0083] As a dosage form other than the aforementioned microcapsule,
an organic solvent solution containing a physiologically active
substance or a salt thereof and a lactic acid-glycolic acid polymer
or a salt thereof described in a method of drying in water in a
method of preparing a microcapsule (I) is dried by evaporating an
organic solvent and water while the degree of vacuum is regulated
using, for example, a rotary evaporator, which may be ground with a
jet mill to obtain a fine powder (also referred to as
microparticle).
[0084] Further, the ground fine powder may be washed by the same
method as that described in a method of drying in water in a method
of preparing a microcapsule (I), lyophilized and further warmed and
dried.
[0085] The thus obtained microcapsule or fine powder can achieve
release of a drug corresponding to a decreasing rate of a lactic
acid-glycolic acid polymer used.
[0086] The sustained-release composition of the present invention
may be any form such as a microsphere, a microcapsule or a fine
powder (microparticle), and a microcapsule is suitable.
[0087] The sustained-release composition of the present invention
may be used as it is or the composition as a raw material may be
formulated into a variety of dosage forms, and may be administered
as an injectable agent or an implantable agent for intravenous,
subcutaneous and intra-organ administration, as a transmucosal
agent, an oral agent (for example, capsule (for example, hard
capsule, soft capsule and the like)), solid preparations such as a
granule, a powder and the like, or liquid agent such as a syrup
agent, an emulsion, a suspension and the like for nasal, rectal or
uterine administration.
[0088] For example, for formulating the sustained-release
composition of the present invention into an injectable agent, it
is formulated into an aqueous suspension together with a dispersant
(for example, surfactants such as Tween 80, HCO-60 and the like,
and polysaccharides such as sodium hyaluronate,
carboxymethylcellulose, sodium arginate and the like), a
preservative (for example, methylparaben and propylparaben), an
isotonic (sodium chloride, mannitol, sorbitol, glucose and
proline), or it is dispersed into an oily suspension together with
a plant oil such as sesame oil or corn oil to obtain a
sustained-release injection agent which can be actually used.
[0089] The particle diameter of a sustained-release composition of
the present invention may be, when used as a suspension injection
agent, in such a range that satisfies a dispersion degree and the
needle penetrating property. For example, an average particle
diameter is a range of about 0.1 to 300 .mu.m, preferably about 0.5
to 150 .mu.m, more preferably about 1 to 100 .mu.m.
[0090] In order to formulate a sustained-release composition of the
present invention into an aseptic preparation, methods include, but
are not limited to a method of performing all steps aseptically in
preparation, a method of sterilizing with gamma-ray, a method of
adding an antiseptic and the like.
[0091] Since a sustained-release composition of the present
invention of low toxicity, it can be used as a safe medicine for a
mammal (for example, human being, cow, pig, dog, cat, mouse, rat,
rabbit and the like), the dose of sustained-release composition of
the present invention can vary depending on the type and content of
the physiologically active substance, the dosage form, duration
time of release of physiologically active substance, target disease
and subject animal and effective amount of a physiologically active
substance. A single dosage of physiologically active substance can
be preferably selected appropriately from a range of about 0.01 mg
to 10 mg/kg weight, more preferably about 0.05 mg to 5 mg/kg weight
per adult, for example, when used in a sustained-release
preparation for a six months preparation.
[0092] A single dose of a sustained-release composition can be
preferably selected appropriately from about 0.05 mg to 50 mg/kg
weight, more preferably about 0.1 mg to 30 mg/kg weight per
adult.
[0093] Administration time can be appropriately selected depending
on the type and content of a physiologically active substance as a
basis, dosage form, duration time of release of a physiologically
active substance, target disease and a subject animal, such as once
every few weeks, once per month, once every few months (for
example, three months, four months, six months etc) and the
like.
[0094] A sustained-release composition of the present invention can
be used as an agent for preventing or treating a variety of
diseases depending on the type of physiologically active substance
contained therein and, for example, when a physiologically active
substance is an LH-RH derivative, it can be used for preventing or
treating hormone dependent diseases, in particular, sex hormone
dependent cancers (for example, prostate cancer, uterine cancer,
breast cancer, pituitary gland tumor and the like), sex hormone
dependent diseases such as prostatomegaly, endometriosis,
hysteromyoma, precocious puberty, dysmenorrhea, amenorrhea,
premenstrual syndrome, multilocular ovary syndrome and the like, as
an agent for preventing recurrence of breast cancer after the
operation for premenopausal breast cancer, as an agent for
preventing or treating Alzheimer's disease or autoimmune diseases,
and as a contraceptive (or, an agent for preventing or treating
infertility, when the rebound activity after cease of
administration is utilized). Further, it can also be used as an
agent for preventing or treating benign or malignant tumors which
are known to be sex hormone independent but sensitive to LH-RH.
[0095] Therefore, hormone dependent diseases, in particular, sex
hormone dependent cancers (for example, prostate cancer, uterine
cancer, breast cancer, pituitary gland tumor and the like), sex
hormone dependent diseases such as prostatomegaly, endometriosis,
hysteromyoma, precocious puberty, dysmenorrhea, amenorrhea,
premenstrual syndrome, multilocular ovary syndrome and the like can
be prevented or treated; and pregnancy can be prevented by
administering to a mammal an effective dose of the treating or
preventing agent according to this invention, and also recurrence
of breast cancer after the operation for premenopausal breast
cancer can be prevented thereby.
EXAMPLES
[0096] The present invention will be explained more specifically by
way of Examples, Comparative Examples and Experimental Examples but
the present invention is not limited by them.
Example A1
[0097] 10 g of a lactic acid-glycolic acid copolymer, having a
weight average molecular weight of 9700 and a number average
molecular weight of 5030, synthesized by dehydration
polycondensation of lactic acid and glycolic acid is dissolved in
100 mL of acetone, and 40 mL of purified water is added dropwise
while stirring, to precipitate a polymer. The solution other than
the precipitated glutinous starch syrup-like polymer is removed by
decantation, and the resulting polymer is dried under vacuum. The
polymer after drying has a yield of 8.37 g, a weight average
molecular weight of 10500, and a number average molecular weight of
6700.
Example A2
[0098] 4.87 g of the polymer obtained in Example A1 is dissolved in
8.03 g of dichloromethane into an oily phase. The oily phase is
mixed into an aqueous phase in which 0.597 g of acetate of Peptide
A is dissolved in 0.6 mL of purified water, which is
primarily-emulsified at 25000 rpm using a Polytron to obtain a W/O
emulsion. This W/O emulsion is added to 1000 mL of an 0.1% aqueous
polyvinyl alcohol solution at 15.degree. C., which is converted
into a W/O/W emulsion at 7000 rpm using a homomixer. The
microcapsule is solidified by desolvation with a propeller stirrer
over three hours, then microcapsules which have passed through a
200 mesh sieve are recovered, and lyophilized after 0.48 g of
mannitol has been added. After lyophilization, the yield of the
resulting microcapsule is 3.92 g and the content of Peptide A is
10.18%.
Comparative Example A1
[0099] A microcapsule obtained using a lactic acid-glycolic acid
copolymer of Example A1 according to the same manner as that of
Example A2 has a yield of 3.97 g, and a content of Peptide A of
9.50%.
Experimental Example A1
[0100] Microcapsules obtained in Example A2 and Comparative Example
A1 were dispersed in 0.3 ml of a dispersing medium (distilled water
in which 0.25 mg of carboxymethylcellulose, 0.5 mg of Polysorbate
80 and 25 mg of mannitol are dissolved) at an amount of 2.25 mg in
terms of Peptide A, which were administered to a male SD rat, 7
weeks old, in the back subcutaneously with a 22G injection needle,
respectively. A prescribed time after administration, rats were
slaughtered, microcapsules remaining in the administration site was
removed, and Peptide A remaining in it was quantitated, which was
divided by each initial content to obtain a remaining rate as shown
in Table 1. Further, Mw/Mn of polymers used in Example A2 and
Comparative Example A1 are described in Table.
TABLE-US-00002 TABLE 1 Comparative Example A1 Example A2 Mw/Mn 1.93
1.57 1 day 84.64% 91.17% 2 week 32.2% 54.31% 4 week 2.54%
10.28%
[0101] It is apparent from Table 1, that when a polymer used in
Example A2 and having Mw/Mn of 1.90 or lower rendered by acetone
treatment is used to prepare a microcapsule, the initial release
amount of Peptide A from the microcapsule is suppressed, and
sustained release over a long term of four weeks is ensured.
Example A3
[0102] 185.7 g of a lactic acid-glycolic acid copolymer having a
weight average molecular weight of 10600 and a number average
molecular weight of 6600 was dissolved in 300.1 g of
dichloromethane, and the temperature was adjusted to 29.5.degree.
C. 330.2 g was weighed from this organic solvent solution, then
mixed with an aqueous solution which had been obtained by
dissolving 15.62 g of acetate of Peptide A in 15.31 g of distilled
water which had been warmed to 54.3.degree. C., and stirred for 1
minute to obtain a crude emulsion, which was next emulsified under
the conditions of 10,000 rpm for two minutes using a homogenizer to
form a W/O emulsion. Then, this W/O emulsion was cooled to
17.8.degree. C., poured into 25 liters of a 0.1% (w/w) aqueous
polyvinyl alcohol (EG-40, manufactured by Nihongoseikagaku)
solution which had been adjusted to 17.9.degree. C. in advance, for
1 minute and 16 seconds, and stirred at 7,005 rpm using HOMOMIC
LINE FLOW (manufactured by Tokushukika) to obtain a W/O/W emulsion.
This W/O/W emulsion was stirred for 3 hours to volatilize
dichloromethane or diffuse dichloromethane into an external aqueous
phase, an oily phase was solidified, filtered through a sieve
having 75 .mu.m opening, and a microcapsule was settled
continuously at 2,000 rmp using a centrifuge (H-600S, manufactured
by Kokusanenshinki) and collected. The collected microcapsule was
dispersed again in a small amount of distilled water, filtered
through a sieve having 90 .mu.m opening, which was dissolved by
addition of 17.2 g of mannitol and lyophilized to obtain a powder.
The microcapsule had a recovery rate of 76.4% and a content of
Peptide A in the microcapsule of 8.79%.
Experimental Example A2
[0103] About 26 mg of a microcapsule described in Example A3 was
dispersed in 0.3 ml of a dispersing medium (distilled water in
which 0.15 mg of carboxymethylcellulose, 0.3 mg of Polysorbate 80
and 15 mg of mannitol are dissolved), which was administered to a
male SD rat, 7 weeks old, in the back subcutaneously with a 22G
injection needle. A prescribed time after administration, the rat
was slaughtered, microcapsule remaining in the administration site
was removed, Peptide A in it was quantitated, which was divided by
each initial content to obtain a remaining rate as shown in Table
2.
TABLE-US-00003 TABLE 2 Time 1 day 1 week 2 weeks 3 weeks 4 weeks 5
weeks Remaining 90.29% 68.06% 36.63% 12.75% 4.48% 1.12% rate
[0104] As apparent from Table 2, even when preparation was scaled
up, although the microcapsule described in Example A3 contains a
physiologically active substance at a high content, the remaining
rate of a physiologically active substance one day after
administration is as remarkably high as 90%. Therefore, when an
Mw/Mn ratio of a polymer is a low value as about 1.6, the effect of
considerably suppressing initial excessive release of a
physiologically active substance is exerted. In addition, this
microcapsule achieves release of the physiologically active
substance at a constant rate over a long period of time.
Example B1
[0105] 197.7 g of a lactic acid-glycolic acid copolymer having a
weight average molecular weight of 12600 and a number average
molecular weight of 6400 was dissolved in 320.1 g of
dichloromethane, press-filtered using a 0.2 .mu.m filter (EMFLOW,
DFA4201FRP), and the temperature was adjusted to about 30.0.degree.
C. 330.1 g was weighed, mixed with an aqueous solution which had
been obtained by dissolving 15.68 g of acetate of Peptide A in
15.31 g of distilled water and had been warmed to 56.0.degree. C.,
stirred for 1 minute to obtain a crude emulsion, which was then
emulsified under the condition of 10,000 rpm for two minutes to
obtain a W/O emulsion. Then, this W/O emulsion was cooled to
18.2.degree. C., poured into 25 liters of a 0.1% (w/w) polyvinyl
alcohol (EG-40, manufactured by Nihongoseikagaku) which had been
adjusted to 18.4.degree. C. in advance, for 1 minute and 46
seconds, stirred at 7,007 rpm using HOMOMIC LINE FLOW (manufactured
by Tokushukika) to obtain a W/O/W emulsion. This W/O/W emulsion was
stirred for 3 hours to volatilize dichloromethane or diffuse it
into an external aqueous phase, then the oily phase was solidified,
filtered using a seive having 75 .mu.m opening, and microcapsule
was continuously settled at 2,000 rpm using a centrifuge (H-600S,
manufactured by Kokusanenshinki) and collected. The collected
microcapsule was dispersed again in a small amount of distilled
water, filtered using a seive having 90 .mu.m opening, then
dissolved by addition of 17.2 g of mannitol and lyophilized to
obtain a powder. The microcapsule had a recovery rate of 73.47% and
a content of Peptide A in a microcapsule of 8.43%.
Experimental Example B1
[0106] About 26.7 mg of the microcapsule described in Example B1
was dispersed in 0.3 mg of dispersing medium (distilled water in
which 0.15 mg of carboxymethylcellulose, 0.3 mg of Polysorbate 80,
and 15 mg of mannitol were dissolved), and administered to a male
SD rat, 7 weeks old, in the back subcutaneously with a 22G
injection needle. A prescribed time after administration, the rat
was slaughtered, and microcapsule remaining at the administration
site, and Peptide A in it was quantitated, which was divided by
each initial content to obtain a remaining rate as shown in Table
3.
TABLE-US-00004 TABLE 3 Time 1 day 1 week 2 weeks 3 weeks 4 weeks 5
weeks Remaining 82.43% 68.33% 47.07% 23.58% 9.05% 2.08% rate
As apparent from Table 3, microcapsule described in Example B1
could contain a physiologically active substance at a high content
even when gelatin was not included, and remarkably suppressed
initial release of a physiologically active substance and, this
microcapsule released a physiologically active substance over a
long period of time.
Experimental Example B2
[0107] About 44.6 mg of a microcapsule described in Example B1 was
dispersed in 1.0 ml of a dispersing medium (distilled water in
which 0.15 mg of carboxymethylcellulose, 0.3 mg of Polysorbate 80,
and 15 mg of mannitol were dissolved), which was administered to a
beagle, weighing 7 to 12 kg, in the back subcutaneously with a 23G
injection needle. A prescribed time after administration, blood was
taken from a forefoot vein, the concentrations of Peptide A and
testosterone were quantitated, and the results are shown in Table
4.
TABLE-US-00005 TABLE 4 Time 1 day 1 week 2 week 3 week 4 week 5
week Peptide A 2.21 0.398 0.525 0.433 0.603 0.358 Testosterone 2.79
0.57 0.35 0.35 0.30 0.39
[0108] As apparent from Table 4, a microcapsule described in
Example B1 releases a physiologically active substance for a long
period of time, and maintained the blood concentration of the
physiologically active substance. In addition, the activity of the
physiologically active substance released into blood was not lost
and drug efficacy was retained.
INDUSTRIAL APPLICABILITY
[0109] A sustained-release preparation of the present invention,
having a ratio of weight average molecular weight to number average
molecular weight of PLGA as a base of about 1.90 or lower, or using
a lactic acid-glycolic acid polymer having weight average molecular
weight of about 11,600 to about 14,000 or a salt thereof as a base,
contains a physiologically active substance in high content even
when gelatin is not included, and suppresses initial excessive
release of physiologically active substance and, thus, can achieve
a stable release rate over about one month.
[0110] That is, the preparation according to this invention has
such useful effects that the manufacturing process and cost can be
reduced because there is no need for using a drug retaining
substance such as gelatin and a thickening agent, resulting reduced
additives, and that the preparation can contain a drug at a high
concentration without using a drug retaining substance and a
thickening agent; a sustained-release composition which releases a
drug over at least two weeks can be produced; and the preparation
having high stability can be produced owing to the increase of
glass transition temperature.
* * * * *