U.S. patent application number 17/315584 was filed with the patent office on 2021-09-02 for self-emulsifying composition of omega3 fatty acid.
This patent application is currently assigned to MOCHIDA PHARMACEUTICAL CO., LTD.. The applicant listed for this patent is MOCHIDA PHARMACEUTICAL CO., LTD.. Invention is credited to Hirosato FUJII, Hiromitsu ITO, Shigeru KIMURA, Motoo YAMAGATA.
Application Number | 20210267927 17/315584 |
Document ID | / |
Family ID | 1000005585078 |
Filed Date | 2021-09-02 |
United States Patent
Application |
20210267927 |
Kind Code |
A1 |
KIMURA; Shigeru ; et
al. |
September 2, 2021 |
SELF-EMULSIFYING COMPOSITION OF OMEGA3 FATTY ACID
Abstract
A self-emulsifying composition contains: 70 to 90% by weight in
total of one or more compounds selected from the group consisting
of .omega.3 polyunsaturated fatty acids and their pharmaceutically
acceptable salts and esters; 1 to 29% by weight of an emulsifying
agent selected from among a polyoxyethylene sorbitan fatty acid
ester, a sorbitan fatty acid ester, a glycerin fatty acid ester and
a polyoxyl castor oil; and 0.5 to 6% by weight of water when the
composition is defined to be 100% by weight as a whole. The
self-emulsifying composition is excellent in self-emulsifying
property, composition dispersibility, emulsion stability, and
absorbability, is free from ethanol and polyhydric alcohols or only
has such an alcohol added thereto at a reduced concentration, and
is useful for foods and pharmaceuticals.
Inventors: |
KIMURA; Shigeru; (Tokyo,
JP) ; ITO; Hiromitsu; (Tokyo, JP) ; FUJII;
Hirosato; (Tokyo, JP) ; YAMAGATA; Motoo;
(Tokyo, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
MOCHIDA PHARMACEUTICAL CO., LTD. |
Tokyo |
|
JP |
|
|
Assignee: |
MOCHIDA PHARMACEUTICAL CO.,
LTD.
Tokyo
JP
|
Family ID: |
1000005585078 |
Appl. No.: |
17/315584 |
Filed: |
May 10, 2021 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16380663 |
Apr 10, 2019 |
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17315584 |
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15684694 |
Aug 23, 2017 |
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16380663 |
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14905520 |
Jan 15, 2016 |
9801843 |
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PCT/JP2014/069115 |
Jul 17, 2014 |
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15684694 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/1075 20130101;
A61K 47/10 20130101; A61K 31/232 20130101; A61K 47/14 20130101;
A61K 31/202 20130101; A23L 33/115 20160801; A61K 47/26 20130101;
A23L 29/10 20160801; A61K 9/4858 20130101 |
International
Class: |
A61K 31/202 20060101
A61K031/202; A61K 31/232 20060101 A61K031/232; A61K 47/26 20060101
A61K047/26; A61K 9/48 20060101 A61K009/48; A23L 29/10 20060101
A23L029/10; A23L 33/115 20060101 A23L033/115; A61K 9/107 20060101
A61K009/107; A61K 47/10 20060101 A61K047/10; A61K 47/14 20060101
A61K047/14 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 18, 2013 |
JP |
2013-149645 |
Claims
1. A self-emulsifying composition comprising, when the
self-emulsifying composition is defined to be 100% by weight as a
whole: a) 70 to 90% by weight of at least one compound selected
from the group consisting of .omega.3 polyunsaturated fatty acids
and their pharmaceutically acceptable salts and esters, b) 0.5 to
6% by weight of water, c) 1 to 29% by weight of an emulsifying
agent comprising i) a polyoxyethylene sorbitan fatty acid ester or
ii) at least two members selected from the group consisting of a
sorbitan fatty acid ester, a glycerin fatty acid ester and a
polyoxyethylene castor oil; or 1 to 29% by weight of an emulsifying
agent comprising i) a polyoxyethylene sorbitan fatty acid ester and
ii) at least one member selected from the group consisting of a
sorbitan fatty acid ester, a glycerin fatty acid ester and a
polyoxyethylene castor oil, wherein d) a content of ethanol is up
to 4% by weight, e) a content of polyhydric alcohol is up to 4% by
weight, and f) a content of lecithin is lower than 2.1% by weight,
wherein the self-emulsifying composition has a non-separated or
non-cloudy appearance and has a transparent appearance when stored
in the environment of 5.degree. C. or 40.degree. C. for 12
hours.
2. The self-emulsifying composition according to claim 1, wherein a
content of lecithin in the composition is 0 parts by weight in
relation to 100 parts by weight of the at least one compound
selected from the group consisting of .omega.3 polyunsaturated
fatty acids and their pharmaceutically acceptable salts and
esters.
3. The self-emulsifying composition according to claim 1, wherein
the .omega.3 polyunsaturated fatty acids and their pharmaceutically
acceptable salts and esters comprise at least one member selected
from the group consisting of eicosapentaenoic acid (EPA),
docosahexaenoic acid (DHA), and their pharmaceutically acceptable
salts and esters.
4. The self-emulsifying composition according to claim 1, wherein
the polyhydric alcohol is propylene glycol or glycerin.
5. The self-emulsifying composition according to claim 1, wherein
the content of the polyhydric alcohol is up to 1% by weight of the
composition.
6. The self-emulsifying composition according to claim 1, wherein
the content of the ethanol is up to 1% by weight of the
composition.
7. The self-emulsifying composition according to claim 1, wherein
the mean droplet diameter when the composition is dispersed in
water is up to 2 .mu.m.
8. A capsulated self-emulsifying preparation comprising a capsule
which comprises a liquid self-emulsifying composition, with the
self-emulsifying composition comprising, when the self-emulsifying
composition is defined to be 100% by weight as a whole: a) 70 to
90% by weight of at least one compound selected from the group
consisting of .omega.3 polyunsaturated fatty acids and their
pharmaceutically acceptable salts and esters, b) 0.5 to 6% by
weight of water, c) 1 to 29% by weight of an emulsifying agent
comprising i) a polyoxyethylene sorbitan fatty acid ester or ii) at
least two members selected from the group consisting of a sorbitan
fatty acid ester, a glycerin fatty acid ester and a polyoxyethylene
castor oil; or 1 to 29% by weight of an emulsifying agent
comprising i) a polyoxyethylene sorbitan fatty acid ester and ii)
at least one member selected from the group consisting of a
sorbitan fatty acid ester, a glycerin fatty acid ester and a
polyoxyethylene castor oil, d) an ethanol content which is up to 4%
by weight of the composition, and e) a polyhydric alcohol content
which is up to 4% by weight of the composition, wherein the
composition comprises essentially no lecithin, and f) a content of
lecithin is lower than 2.1% by weight of the composition, wherein
the self-emulsifying composition has a non-separated or non-cloudy
appearance and has a transparent appearance when stored in the
environment of 5.degree. C. or 40.degree. C. for 12 hours, and
wherein the capsule is a hard capsule or a soft capsule.
9. The capsulated self-emulsifying preparation according to claim
8, wherein the capsule is a soft capsule and a capsule film of the
soft capsule comprises gelatin.
10. The capsulated self-emulsifying preparation according to claim
8, wherein a content of lecithin in the self-emulsifying
composition is 0 parts by weight in relation to 100 parts by weight
of the at least one compound selected from the group consisting of
.omega.3 polyunsaturated fatty acids and their pharmaceutically
acceptable salts and esters.
11. The capsulated self-emulsifying preparation according to claim
8, wherein the .omega.3 polyunsaturated fatty acids and their
pharmaceutically acceptable salts and esters comprise at least one
member selected from the group consisting of eicosapentaenoic acid
(EPA), docosahexaenoic acid (DHA), and their pharmaceutically
acceptable salts and esters.
12. The capsulated self-emulsifying preparation according to claim
8, wherein the polyhydric alcohol is propylene glycol or
glycerin.
13. The capsulated self-emulsifying preparation according to claim
8, wherein the content of the polyhydric alcohol is up to 1% by
weight of the composition.
14. The capsulated self-emulsifying preparation according to claim
8, wherein the content of the ethanol is up to 1% by weight of the
composition.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a Continuation of copending application
Ser. No. 16/380,663, filed Apr. 10, 2019, which is a continuation
of application Ser. No. 15/684,694, filed Aug. 23, 2017, which is a
Continuation of copending application Ser. No. 14/905,520, filed on
Jan. 15, 2016, now U.S. Pat. No. 9,801,843, which is the National
Phase under 35 U.S.C. .sctn. 371 of International Application No.
PCT/JP2014/069115, filed on Jul. 17, 2014, which claims the benefit
under 35 U.S.C. .sctn. 119(a) to Patent Application No.
2013-149645, filed in Japan on Jul. 18, 2013, all of which are
hereby expressly incorporated by reference into the present
application.
TECHNICAL FIELD
[0002] This invention provides a self-emulsifying composition
containing at least one member selected from the group consisting
of .omega.3 polyunsaturated fatty acids and their pharmaceutically
acceptable salts and esters. This invention also provides a
pharmaceutical product using such a composition, and production and
application methods thereof.
BACKGROUND ART
[0003] Known .omega.3 polyunsaturated fatty acids (hereinafter
abbreviated as .omega.3 PUFA) include .alpha.-linolenic acid,
eicosapentaenoic acid (hereinafter abbreviated as EPA), and
docosahexaenoic acid (hereinafter abbreviated as DHA). Since the
.omega.3 PUFA and pharmaceutically acceptable salts and esters
thereof have actions such as anti-arteriosclerosis action, platelet
aggregation suppressive action, blood lipid lowering action,
anti-inflammatory action, carcinostatic action, and central action,
they are blended in various food products, and commercially sold in
the form of health food and medical and pharmaceutical
products.
[0004] Ethyl eicosapentaenoate ester (hereinafter abbreviated as
EPA-E) is commercially sold in Japan as an oral therapeutic agent
for ameliorating ulcer, pain, and coldness associated with
arteriosclerosis obliterans as well as hyperlipidemia (product name
Epadel, Mochida Pharmaceutical Co., Ltd.). When EPA-E is orally
administered under fasting, increase in plasma EPA concentration is
smaller than the case of the oral administration after the meal
conceivably because absorption of the EPA-E requires secretion of
bile acid and food components as a carrier. Accordingly, Epadel is
instructed to be orally administered immediately after the meal
(see Non-Patent Literature 1).
[0005] However, dosage method or drug compliance has become a
problem for those people not taking breakfast with the recent
change in the life style, patients who can only take meals at a
reduced amount, patients who can only take a fluid diet (milk, rice
broth, starch gruel, egg, soup, juice, or oral nutritional
supplement), patients with reduced absorption ability of the
intestinal tract (for example, elderly, patients of intestinal
disease, patients after intestinal surgery, terminal cancer
patients, and patients taking a lipase inhibitor), or patients who
are unable to take meals such as those after the cerebral
infarction.
[0006] Recent attention is being drawn to the relationship of the
condition where the serum triglyceride (hereafter abbreviated as
TG) level is abnormally increased after meals while being normal
upon fasting, or non-fasting hypertriglyceridemia with a
prolongation of such abnormal increase, to coronary artery disease,
and it is desired to develop an .omega.3 PUFA preparation rapidly
absorbable even if administered before meals and capable of
suppressing the increase in serum TG level after meals.
[0007] A self-emulsifying preparation which does not contain water
in the preparation and which is readily dispersible and
self-emulsifying when brought into contact with water has been
reported (see Patent Literature 1 and Non-Patent Literature 4).
This preparation contains an .omega.3 PUFA and fenofibrate as its
effective components, ethanol, and a surfactant.
[0008] These compositions contain ethanol as a component added for
improving the dissolution of the fenofibrate. However,
volatilization of the ethanol is associated with the risk of
capsule deformation and bubble inclusion in the capsule, damages in
the quality such as capsule deformation and cracks, as well as
denaturing of the content in the capsule such as cloudiness and
separation. In addition, use of a preparation containing such
composition should be difficult if not impossible for patients
intolerable for the alcohol (ethanol).
[0009] A self-emulsifying composition containing ethanol and
polyhydric alcohols in addition to the .omega.3 PUFA and a
surfactant which is capable of forming a dispersion having a small
or very small average particle size when brought in contact with
water is also reported (Patent Literature 2).
[0010] With regard to self-emulsifying compositions having a low
ethanol content, a self-emulsifying composition comprising an
.omega.3 PUFA, an emulsifier having a hydrophile lipophile balance
(hereinafter abbreviated as HLB) of at least 10, lecithin, and a
polyhydric alcohol such as propylene glycol or glycerin which has
high self-emulsifying property, oral fasting absorbability and
absorption speed has been reported (Patent Literature 3).
[0011] When a composition containing a co-solvent such as a
polyhydric alcohol is encapsulated in a capsule, the co-solvent
moves to the capsule film to cause denaturing of the composition as
well as capsule deformation due to the softening of the capsule
(Patent Literature 4).
[0012] Self-emulsifying compositions, as generally containing
larger amounts of emulsifiers and, accordingly, being increased in
total amount, are liable to cause inflammation of the
gastrointestinal tract or have a reduced content per capsule of the
biologically active component dissolved in oil component (Patent
Literature 5). Accordingly, the emulsifier used in the
self-emulsifying composition is preferably the one which is
non-toxic or less-toxic even in the case of continuous
administration, and the emulsifier is preferably used at a low
content.
[0013] In view of compliance, amount of the emulsifier and alcohols
incorporated should be minimized also in consideration of reducing
the size of the preparation because amount of the preparation that
has to be taken per administration increases with the increase in
the amount of the components other than the .omega.3 PUFA in the
self-emulsifying composition since predetermined amount of the
.omega.3 PUFA should be taken per administration.
CITATION LIST
Patent Literatures
[0014] Patent Literature 1: JP 2008-516890 A
[0015] Patent Literature 2: JP 2012-519728 A
[0016] Patent Literature 3: WO 2010/134614
[0017] Patent Literature 4: JP 2011-12003 A
[0018] Patent Literature 5: JP 2012-180337 A
NON-PATENT LITERATURES
[0019] Non-Patent Literature 1: Epadel S (Drug Interview Form),
Mochida Pharmaceutical Co., Ltd., June, 2012
[0020] Non-Patent Literature 2: "Guideline for Diagnosis and
Prevention of Atherosclerotic Cardiovascular Diseases, 2007
Edition" edited by Japan Atherosclerosis Society and published by
Kyowa Kikaku Ltd., Apr. 25, 2007
[0021] Non-Patent Literature 3: Diabetes, vol. 57, No. 9,
2382-2392, 2008
[0022] Non-Patent Literature 4: European Journal of Pharmaceutical
Sciences, vol. 33, 351-360, 2008
[0023] Non-Patent Literature 5: "2007 Dictionary of Drug Additives"
edited by International Pharmaceutical Excipients Council Japan and
published by Yakuji Nippo Ltd., Jul. 25, 2007
SUMMARY OF INVENTION
Technical Problems
[0024] There is a demand for a preparation wherein ethanol and
polyhydric alcohols added to the self-emulsifying composition have
been reduced.
[0025] There is also a demand for a preparation wherein emulsifier
added to the self-emulsifying composition has been reduced.
[0026] There is also a demand for a preparation wherein content of
the .omega.3 PUFA in the self-emulsifying composition has been
increased.
[0027] There is also a demand for a self-emulsifying composition
which shows excellent drug compliance.
[0028] There is also a demand for a self-emulsifying composition
which is free from denaturing such as cloudiness and separation and
which retains the good appearance during its storage at room
temperature, and also, at low temperature and high temperature
environments since use of the self-emulsifying composition as a
drug may involve storage in cold district and other
environments.
[0029] There is also a demand for a self-emulsifying composition
wherein the composition has stable quality.
[0030] There is also a demand for a preparation wherein the
self-emulsifying composition has been encapsulated.
[0031] There is also a demand for a preparation wherein softening
of the capsule film after the encapsulation of the self-emulsifying
composition is suppressed so that the capsulated preparation is not
deformed.
[0032] Accordingly, an object of the present invention is to
provide a self-emulsifying composition which has realized one or
more of the demands as described above. Another object of the
present invention is to provide a preparation encapsulating such
composition.
Solution to Problems
[0033] In view of the problems as described above, the inventors of
the present invention made an intensive investigation on the
components which would be substitutes for the ethanol and the
polyhydric alcohols, and found that a predetermined amount of water
is useful in improving the compatibility of the self-emulsifying
composition.
[0034] The inventors also found that the content of the emulsifying
agent can be further reduced, and a self-emulsifying composition
having a high content of the .omega.3 PUFA was thereby completed.
The present invention has been completed on the basis of such
findings.
[0035] The composition of the present invention is a composition
which exhibits excellent properties with regard to at least one of
the problems as described above.
[0036] Accordingly, a first aspect of the present invention is the
self-emulsifying composition as described below.
[0037] (1-1) A self-emulsifying composition comprising, when the
self-emulsifying composition is defined to be 100% by weight as a
whole,
[0038] a) 70 to 90% by weight of at least one compound selected
from the group consisting of .omega.3 polyunsaturated fatty acids
and their pharmaceutically acceptable salts and esters,
[0039] b) 0.5 to 6% by weight of water, and
[0040] c) 1 to 29% by weight of an emulsifying agent including
either [0041] i) a polyoxyethylene sorbitan fatty acid ester or
[0042] ii) at least two members selected from the group consisting
of a sorbitan fatty acid ester, a glycerin fatty acid ester and a
polyoxyethylene castor oil, or
[0043] 1 to 29% by weight of an emulsifying agent including [0044]
i) a polyoxyethylene sorbitan fatty acid ester and [0045] ii) at
least one member selected from the group consisting of a sorbitan
fatty acid ester, a glycerin fatty acid ester and a polyoxyethylene
castor oil, wherein
[0046] d) content of ethanol and/or polyhydric alcohol is up to 4%
by weight of the whole composition.
[0047] (1-2) A self-emulsifying composition comprising, when the
self-emulsifying composition is defined to be 100% by weight as a
whole,
[0048] a) 70 to 90% by weight of at least one compound selected
from the group consisting of .omega.3 polyunsaturated fatty acids
and their pharmaceutically acceptable salts and esters,
[0049] b) 0.5 to 6% by weight of water, and
[0050] c) 1 to 29% by weight of an emulsifying agent including
either [0051] i) a polyoxyethylene sorbitan fatty acid ester or
[0052] ii) at least two members selected from the group consisting
of a sorbitan fatty acid ester, a glycerin fatty acid ester and a
polyoxyethylene castor oil, or
[0053] 1 to 29% by weight of an emulsifying agent including [0054]
i) a polyoxyethylene sorbitan fatty acid ester and [0055] ii) at
least one member selected from the group consisting of a sorbitan
fatty acid ester, a glycerin fatty acid ester and a polyoxyethylene
castor oil, wherein
[0056] d) content of ethanol is up to 4% by weight of the whole
composition, and
[0057] e) content of polyhydric alcohol is up to 4% by weight of
the whole composition.
[0058] (1-3) A self-emulsifying composition according to (1-1) or
(1-2), wherein the polyoxyethylene sorbitan fatty acid ester is at
least one member selected from the group consisting of
polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20)
sorbitan monopalmitate, polyoxyethylene (20) sorbitan monostearate,
polyoxyethylene (20) sorbitan tristearate, polyoxyethylene (20)
sorbitan monoisostearate, polyoxyethylene (20) sorbitan monooleate,
and polyoxyethylene (20) sorbitan trioleate.
[0059] (1-4) A self-emulsifying composition according to any one of
(1-1) to (1-3), wherein the sorbitan fatty acid ester is at least
one member selected from the group consisting of sorbitan
monolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitan
trioleate and sorbitan sesquioleate.
[0060] (1-5) A self-emulsifying composition according to any one of
(1-1) to (1-4), wherein the glycerin fatty acid ester is at least
one member selected from the group consisting of glyceryl
monooleate, glyceryl monostearate, decaglyceryl monooleate,
decaglyceryl monolaurate, decaglyceryl trioleate, decaglyceryl
pentaoleate and tetraglyceryl monooleate.
[0061] (1-6) A self-emulsifying composition according to any one of
(1-1) to (1-5), wherein the polyhydric alcohol is propylene glycol
or glycerin.
[0062] (1-7) A self-emulsifying composition according to any one of
(1-1) to (1-5), wherein the composition contains 0 to 4% by weight
of the polyhydric alcohol.
[0063] (1-8) A self-emulsifying composition according to any one of
(1-1) to (1-5), wherein the composition does not contain more than
4% by weight of the polyhydric alcohol.
[0064] (1-9) A self-emulsifying composition according to any one of
(1-1) to (1-8), wherein the content of the polyhydric alcohol in
the composition is up to 1% by weight.
[0065] (1-10) A self-emulsifying composition according to any one
of (1-1) to (1-8), wherein the composition contains 0 to 1% by
weight of the polyhydric alcohol.
[0066] (1-11) A self-emulsifying composition according to any one
of (1-1) to (1-8), wherein the composition does not contain more
than 1% by weight of the polyhydric alcohol.
[0067] (1-12) A self-emulsifying composition according to any one
of (1-1) to (1-11), wherein the composition contains substantially
no polyhydric alcohol.
[0068] (1-13) A self-emulsifying composition according to any one
of (1-1) to (1-12), wherein the content of the ethanol in the
composition is up to 4% by weight.
[0069] (1-14) A self-emulsifying composition according to any one
of (1-1) to (1-12), wherein the composition contains 0 to 4% by
weight of the ethanol.
[0070] (1-15) A self-emulsifying composition according to any one
of (1-1) to (1-12), wherein the composition does not contain more
than 4% by weight of the ethanol.
[0071] (1-16) A self-emulsifying composition according to any one
of (1-1) to (1-15), wherein the composition contains substantially
no ethanol.
[0072] (1-17) A self-emulsifying composition according to any one
of (1-1) to (1-16), wherein the .omega.3 PUFAs and their
pharmaceutically acceptable salts and esters include at least one
member selected from the group consisting of EPA, DHA, and their
pharmaceutically acceptable salts and esters.
[0073] (1-18) A self-emulsifying composition according to any one
of (1-1) to (1-17), wherein the esters of the .omega.3 PUFAs are
ethyl esters or triglyceride esters.
[0074] (1-19) A self-emulsifying composition according to any one
of (1-1) to (1-18), wherein EPA-E or ethyl DHA ester (hereinafter
abbreviated as DHA-E) is selected from among the .omega.3 PUFAs and
their pharmaceutically acceptable salts and esters.
[0075] (1-20) A self-emulsifying composition according to any one
of (1-1) to (1-19), which contains at least one member selected
from the group consisting of EPA, DHA, and their pharmaceutically
acceptable salts and esters as its effective component.
[0076] (1-21) A self-emulsifying composition according to any one
of (1-1) to (1-20), which contains EPA-E and/or DHA-E as its
effective component.
[0077] (1-22) A self-emulsifying composition according to any one
of (1-1) to (1-21), which contains EPA-E as its effective
component.
[0078] (1-23) A self-emulsifying composition according to any one
of (1-1) to (1-22), wherein the composition contains less than 3
parts by weight of lecithin in relation to 100 parts by weight of
the at least one compound selected from the group consisting of
.omega.3 PUFAs and their pharmaceutically acceptable salts and
esters.
[0079] (1-24) A self-emulsifying composition according to any one
of (1-1) to (1-23), wherein the composition contains no
lecithin.
[0080] (1-25) A self-emulsifying composition according to (1-23),
wherein the lecithin is at least one member selected from the group
consisting of soybean lecithin, zymolytic soybean lecithin,
hydrogenated soybean lecithin, and egg yolk lecithin.
[0081] (1-26) A self-emulsifying composition according to any one
of (1-1) to (1-25), which has a transparent appearance when allowed
to stand.
[0082] (1-27) A self-emulsifying composition according to any one
of (1-1) to (1-26), which has a non-separated or non-cloudy
appearance when allowed to stand.
[0083] (1-28) A self-emulsifying composition according to any one
of (1-1) to (1-27), which has a transparent appearance when stored
in the environment of 5.degree. C. or 40.degree. C. for 12
hours.
[0084] (1-29) A self-emulsifying composition according to any one
of (1-1) to (1-28), which has a non-separated or non-cloudy
appearance when stored in the environment of 5.degree. C. or
40.degree. C. for 12 hours.
[0085] (1-30) A self-emulsifying composition according to any one
of (1-1) to (1-29), which is excellent in at least one out of
self-emulsifying property, composition dispersibility, and emulsion
stability.
[0086] (1-31) A self-emulsifying composition according to any one
of (1-1) to (1-30), which spontaneously emulsifies when 10 .mu.L of
the composition is added dropwise to 5 mL of purified water or
first fluid for dissolution test of Japanese Pharmacopeia at
37.degree. C.
[0087] (1-32) A self-emulsifying composition according to any one
of (1-1) to (1-31), which is dispersed by agitation when 10 .mu.L
of the composition is added dropwise to 5 mL of purified water or
first fluid for dissolution test of Japanese Pharmacopeia at
37.degree. C.
[0088] (1-33) A self-emulsifying composition according to any one
of (1-1) to (1-32), wherein separation of the oil component does
not occur when 10 .mu.L of the composition is added dropwise to 5
mL of purified water or first fluid for dissolution test of
Japanese Pharmacopeia at 37.degree. C.
[0089] (1-34) A self-emulsifying composition according to any one
of (1-1) to (1-33), wherein, when the self-emulsifying composition
according to any one of (1-1) to (1-33) is orally administered to a
male beagle which has been fasted for at least 18 hours in an
amount corresponding to 600 mg of the at least one compound
selected from the group consisting of .omega.3 PUFAs and their
pharmaceutically acceptable salts and esters, the maximum blood
.omega.3 PUFA concentration is at least 50 .mu.g/mL and/or the area
under the blood .omega.3 PUFA concentration vs time curve from zero
to two hours after the administration is at least 30 .mu.g/mLhr, or
the maximum blood .omega.3 PUFA concentration is at least 50
.mu.g/mL and/or the area under the blood .omega.3 PUFA
concentration vs time curve from zero to two hours after the
administration is at least 50 .mu.g/mLhr, or the maximum blood
.omega.3 PUFA concentration is at least 60 .mu.g/mL and/or the area
under the blood .omega.3 PUFA concentration vs time curve from zero
to two hours after the administration is at least 60 .mu.g/mLhr, or
the maximum blood .omega.3 PUFA concentration is at least 70
.mu.g/mL and/or the area under the blood .omega.3 PUFA
concentration vs time curve from zero to two hours after the
administration is at least 70 .mu.g/mLhr, as calculated with
correction by subtraction of the blood .omega.3 polyunsaturated
fatty acid concentration before the administration of the
composition.
[0090] (1-35) A self-emulsifying composition according to any one
of (1-1) to (1-33), wherein, when the self-emulsifying composition
according to any one of (1-1) to (1-33) is orally administered to a
male crab-eating macaque which has been fasted for at least 12
hours in an amount corresponding to 45 mg/kg body weight of the at
least one compound selected from the group consisting of .omega.3
PUFAs and their pharmaceutically acceptable salts and esters, the
maximum blood .omega.3 PUFA concentration is at least 50 .mu.g/mL
and/or the area under the blood .omega.3 PUFA concentration vs time
curve from zero to 12 hours after the administration is at least
400 .mu.g/mLhr, or the maximum blood .omega.3 PUFA concentration is
at least 70 .mu.g/mL and/or the area under the blood .omega.3 PUFA
concentration vs time curve from zero to 12 hours after the
administration is at least 500 .mu.g/mLhr, as calculated with
correction by subtraction of the blood .omega.3 polyunsaturated
fatty acid concentration before the administration of the
composition.
[0091] (1-36) A self-emulsifying composition according to any one
of (1-1) to (1-33), wherein, when the self-emulsifying composition
according to any one of (1-1) to (1-33) is orally administered to a
human before meals in an amount corresponding to 1800 mg of the at
least one compound selected from the group consisting of .omega.3
PUFAs and their pharmaceutically acceptable salts and esters, the
maximum blood .omega.3 PUFA concentration is at least 50 .mu.g/mL
and/or the blood .omega.3 PUFA concentration two hours after the
administration is at least 10 .mu.g/mL, as calculated with
correction by subtraction of the blood .omega.3 polyunsaturated
fatty acid concentration before the administration of the
composition.
[0092] (1-37) A self-emulsifying composition according to any one
of (1-1) to (1-33), wherein, when the self-emulsifying composition
according to any one of (1-1) to (1-33) is orally administered to a
human before meals in an amount corresponding to 1800 mg of the at
least one compound selected from the group consisting of .omega.3
PUFAs and their pharmaceutically acceptable salts and esters, the
maximum blood .omega.3 PUFA concentration is at least 10 .mu.g/mL
and/or the area under the blood .omega.3 PUFA concentration vs time
curve from zero to 72 hours after the administration is at least
250 .mu.g/mLhr, as calculated with correction by subtraction of the
blood .omega.3 polyunsaturated fatty acid concentration before the
administration of the composition.
[0093] (1-38) A self-emulsifying composition comprising, when the
self-emulsifying composition is defined to be 100% by weight as a
whole,
[0094] a) 70 to 90% by weight of EPA-E,
[0095] b) 0.5 to 6% by weight of water, and
[0096] c) 1 to 29% by weight of an emulsifying agent including
either [0097] i) a polyoxyethylene sorbitan fatty acid ester or
[0098] ii) at least two members selected from the group consisting
of a sorbitan fatty acid ester, a glycerin fatty acid ester and a
polyoxyethylene castor oil, or
[0099] 1 to 29% by weight of an emulsifying agent including [0100]
i) a polyoxyethylene sorbitan fatty acid ester and [0101] ii) at
least one member selected from the group consisting of a sorbitan
fatty acid ester, a glycerin fatty acid ester and a polyoxyethylene
castor oil, wherein
[0102] d) content of ethanol and/or polyhydric alcohol is up to 4%
by weight of the whole composition, and
[0103] e) content of lecithin is less than 3 parts by weight in
relation to 100 parts by weight of a).
[0104] (1-39) A self-emulsifying composition comprising, when the
self-emulsifying composition is defined to be 100% by weight as a
whole,
[0105] a) 70 to 90% by weight of EPA-E,
[0106] b) 0.5 to 6% by weight of water, and
[0107] c) 1 to 29% by weight of an emulsifying agent including
either [0108] i) a polyoxyethylene sorbitan fatty acid ester or
[0109] ii) at least two members selected from the group consisting
of a sorbitan fatty acid ester, a glycerin fatty acid ester and a
polyoxyethylene castor oil, or
[0110] 1 to 29% by weight of an emulsifying agent including [0111]
i) a polyoxyethylene sorbitan fatty acid ester and [0112] ii) at
least one member selected from the group consisting of a sorbitan
fatty acid ester, a glycerin fatty acid ester and a polyoxyethylene
castor oil, wherein
[0113] d) content of ethanol is up to 4% by weight of the whole
composition,
[0114] e) content of polyhydric alcohol is up to 4% by weight of
the whole composition, and
[0115] f) content of lecithin is less than 3 parts by weight in
relation to 100 parts by weight of a).
[0116] A second aspect of the present invention is the capsulated
self-emulsifying preparation as described below.
[0117] (2-1) A capsulated self-emulsifying preparation having the
self-emulsifying composition according to any one of (1-1) to
(1-39) encapsulated in a hard capsule and/or a soft capsule as a
liquid content.
[0118] (2-2) A capsulated self-emulsifying preparation according to
(2-1), which exhibits sufficient hardness immediately after its
production.
[0119] (2-3) A capsulated self-emulsifying preparation according to
(2-1) or (2-2), which has a hardness of 18 kgf or more immediately
after its production.
[0120] (2-4) A capsulated self-emulsifying preparation according to
any one of (2-1) to (2-3), which does not experience loss of its
hardness of 6 kgf or more when sealed in an aluminum package and
stored at 40.degree. C. for 1 week, and then compared with the
preparation before the storage.
[0121] (2-5) A capsulated self-emulsifying preparation according to
any one of (2-1) to (2-4), which has a hardness of 20 kgf or more
when sealed in an aluminum package and stored at 40.degree. C. for
1 week.
[0122] (2-6) A capsulated self-emulsifying preparation according to
any one of (2-1) to (2-5), which, when sealed in an aluminum
package and stored at 40.degree. C. for 1 week, retains 60% or more
of its hardness before the storage.
[0123] (2-7) A preparation according to (2-1), which serves as at
least one drug selected from the group consisting of therapeutic
agent for dyslipidemia (hypercholesterolemia, LDL
hypercholesterolemia, non-HDL hypercholesterolemia, VLDL
hypercholesterolemia, HDL hypocholesterolemia,
hypertriglyceridemia, apo B hyperlipoproteinemia, apo A-I
hypolipoproteinemia, and so forth), therapeutic agent for
postprandial hypertriglyceridemia, anti-arteriosclerosis agent,
platelet aggregation suppressant, therapeutic agent for peripheral
circulatory insufficiency, prophylactic agent for cardiovascular
events, therapeutic agent for inflammatory disease (non-alcoholic
fatty liver disease (hereafter abbreviated as NAFLD), non-alcoholic
steatohepatitis (hereafter abbreviated as NASH), and so forth),
progression suppressant and therapeutic agent for cognitive
impairment (dementia of the Alzheimer's type, cerebrovascular
dementia, mixed type of dementia, and so forth), anticancer agent,
and therapeutic agent for central disease (depression, depressive
condition, obsessive-compulsive disorder, social anxiety disorder,
panic disorder, and so forth).
[0124] A third aspect of the present invention is the method for
producing a self-emulsifying composition as described below.
[0125] (3-1) A method for producing a self-emulsifying composition,
comprising the step of:
[0126] mixing the following components a) to c) in any order while
defining the self-emulsifying composition to be 100% by weight as a
whole,
[0127] a) 70 to 90% by weight of at least one compound selected
from the group consisting of .omega.3 polyunsaturated fatty acids
and their pharmaceutically acceptable salts and esters,
[0128] b) 0.5 to 6% by weight of water, and
[0129] c) 1 to 29% by weight of an emulsifying agent including
either [0130] i) a polyoxyethylene sorbitan fatty acid ester or
[0131] ii) at least two members selected from the group consisting
of a sorbitan fatty acid ester, a glycerin fatty acid ester and a
polyoxyethylene castor oil, or
[0132] 1 to 29% by weight of an emulsifying agent including [0133]
i) a polyoxyethylene sorbitan fatty acid ester and [0134] ii) at
least one member selected from the group consisting of a sorbitan
fatty acid ester, a glycerin fatty acid ester and a polyoxyethylene
castor oil, so that, in the resultant composition,
[0135] d) content of ethanol and/or polyhydric alcohol may be up to
4% by weight of the whole composition.
[0136] (3-2) A method for producing a self-emulsifying composition,
comprising the step of:
[0137] mixing the following components a) to c) in any order while
defining the self-emulsifying composition to be 100% by weight as a
whole,
[0138] a) 70 to 90% by weight of at least one compound selected
from the group consisting of .omega.3 polyunsaturated fatty acids
and their pharmaceutically acceptable salts and esters,
[0139] b) 0.5 to 6% by weight of water, and
[0140] c) 1 to 29% by weight of an emulsifying agent including
either [0141] i) a polyoxyethylene sorbitan fatty acid ester or
[0142] ii) at least two members selected from the group consisting
of a sorbitan fatty acid ester, a glycerin fatty acid ester and a
polyoxyethylene castor oil, or
[0143] 1 to 29% by weight of an emulsifying agent including [0144]
i) a polyoxyethylene sorbitan fatty acid ester and [0145] ii) at
least one member selected from the group consisting of a sorbitan
fatty acid ester, a glycerin fatty acid ester and a polyoxyethylene
castor oil, so that, in the resultant composition,
[0146] d) content of ethanol may be up to 4% by weight of the whole
composition, and
[0147] e) content of polyhydric alcohol may be up to 4% by weight
of the whole composition.
[0148] (3-3) A method for producing a self-emulsifying composition
according to (3-1) or (3-2), further comprising the step of heating
the a), b), and/or c) to a temperature of 70.degree. C. or higher
before the mixing step.
[0149] A fourth aspect of the present invention is the
pharmaceutical preparation as described below for administering a
self-emulsifying composition by a particular method.
[0150] (4-1) A preparation for orally administering at least one
self-emulsifying composition or capsulated self-emulsifying
preparation, drug or veterinary drug selected from among those
according to (1-1) to (1-39), (2-1) to (2-7) and (3-1) to (3-3)
under fasting or at bedtime.
[0151] (4-2) A preparation for orally administering the
self-emulsifying composition or capsulated self-emulsifying
preparation, drug or veterinary drug as produced by the production
method according to any one of (3-1) to (3-3) under fasting or at
bedtime.
[0152] (4-3) A preparation according to (4-1) or (4-2), which
serves as at least one member selected from the group consisting of
therapeutic agent for dyslipidemia (hypercholesterolemia, LDL
hypercholesterolemia, non-HDL hypercholesterolemia, VLDL
hypercholesterolemia, HDL hypocholesterolemia,
hypertriglyceridemia, apo B hyperlipoproteinemia, apo A-I
hypolipoproteinemia, and so forth), therapeutic agent for
postprandial hypertriglyceridemia, anti-arteriosclerosis agent,
platelet aggregation suppressant, therapeutic agent for peripheral
circulatory insufficiency, prophylactic agent for cardiovascular
events, therapeutic agent for inflammatory disease (NAFLD, NASH,
and so forth), progression suppressant and therapeutic agent for
cognitive impairment (dementia of the Alzheimer's type,
cerebrovascular dementia, mixed type of dementia, and so forth),
anticancer agent, as well as prophylactic agent, therapeutic agent
and progression preventing agent for central disease (depression,
depressive condition, obsessive-compulsive disorder, social anxiety
disorder, panic disorder, and so forth).
[0153] (4-4) A preparation according to any one of (4-1) to (4-3),
which is administered once a day.
[0154] (4-5) A method for administering and/or using the
preparation according to any one of (4-1) to (4-4).
[0155] (4-6) A method for increasing the concentration of .omega.3
PUFA in plasma by the oral administration as stated in any one of
(4-1) to (4-4).
[0156] A fifth aspect of the present invention is a method of
prophylaxis, progression prevention, and therapy for at least one
disease selected from the group below.
[0157] (5-1) A method of prophylaxis, progression prevention, and
therapy for at least one disease selected from the group consisting
of dyslipidemia (hypercholesterolemia, LDL hypercholesterolemia,
non-HDL hypercholesterolemia, VLDL hypercholesterolemia, HDL
hypocholesterolemia, hypertriglyceridemia, apo B
hyperlipoproteinemia, apo A-I hypolipoproteinemia, and so forth),
postprandial hypertriglyceridemia, arteriosclerosis, increase of
platelet aggregation, peripheral circulatory insufficiency, onset
of a cardiovascular event, inflammatory disease (NAFLD, NASH, and
so forth), cognitive impairment (dementia of the Alzheimer's type,
cerebrovascular dementia, mixed type of dementia, and so forth),
cancer, and central disease (depression, depressive condition,
obsessive-compulsive disorder, social anxiety disorder, panic
disorder, and so forth), comprising the step of orally
administering at least one self-emulsifying composition or
capsulated self-emulsifying preparation, drug or veterinary drug
selected from among those according to (1-1) to (1-39), (2-1) to
(2-7) and (3-1) to (3-3) to a patient.
[0158] (5-2) A method according to (5-1), wherein the
self-emulsifying composition or capsulated self-emulsifying
preparation, drug or veterinary drug is orally administered under
fasting or at bedtime.
[0159] (5-3) A method according to (5-1) or (5-2), wherein the
self-emulsifying composition or capsulated self-emulsifying
preparation, drug or veterinary drug is administered once a
day.
[0160] A sixth aspect of the present invention is the
self-emulsifying composition as described below.
[0161] (6-1) A self-emulsifying composition, wherein, when the
self-emulsifying composition is orally administered to a male
beagle which has been fasted for at least 18 hours in an amount
corresponding to 600 mg of at least one compound selected from the
group consisting of .omega.3 PUFAs and their pharmaceutically
acceptable salts and esters, the maximum blood .omega.3 PUFA
concentration is at least 50 .mu.g/mL and/or the area under the
blood .omega.3 PUFA concentration vs time curve from zero to two
hours after the administration is at least 30 .mu.g/mL hr, or the
maximum blood .omega.3 PUFA concentration is at least 50 .mu.g/mL
and/or the area under the blood .omega.3 PUFA concentration vs time
curve from zero to two hours after the administration is at least
50 .mu.g/mLhr, or the maximum blood .omega.3 PUFA concentration is
at least 60 .mu.g/mL and/or the area under the blood .omega.3 PUFA
concentration vs time curve from zero to two hours after the
administration is at least 60 .mu.g/mLhr, or the maximum blood
.omega.3 PUFA concentration is at least 70 .mu.g/mL and/or the area
under the blood .omega.3 PUFA concentration vs time curve from zero
to two hours after the administration is at least 70 .mu.g/mLhr, as
calculated with correction by subtraction of the blood .omega.3
polyunsaturated fatty acid concentration before the administration
of the composition.
[0162] (6-2) A self-emulsifying composition, wherein, when the
self-emulsifying composition is orally administered to a male
crab-eating macaque which has been fasted for at least 12 hours in
an amount corresponding to 45 mg/kg body weight of at least one
compound selected from the group consisting of .omega.3 PUFAs and
their pharmaceutically acceptable salts and esters, the maximum
blood .omega.3 PUFA concentration is at least 50 .mu.g/mL and/or
the area under the blood .omega.3 PUFA concentration vs time curve
from zero to 12 hours after the administration is at least 400
.mu.g/mLhr, or the maximum blood .omega.3 PUFA concentration is at
least 70 .mu.g/mL and/or the area under the blood .omega.3 PUFA
concentration vs time curve from zero to 12 hours after the
administration is at least 500 .mu.g/mLhr, as calculated with
correction by subtraction of the blood .omega.3 polyunsaturated
fatty acid concentration before the administration of the
composition.
[0163] (6-3) A self-emulsifying composition, wherein, when the
self-emulsifying composition is orally administered to a human
before meals in an amount corresponding to 1800 mg of at least one
compound selected from the group consisting of .omega.3 PUFAs and
their pharmaceutically acceptable salts and esters, the maximum
blood .omega.3 PUFA concentration is at least 50 .mu.g/mL and/or
the blood .omega.3 PUFA concentration two hours after the
administration is at least 10 .mu.g/mL, as calculated with
correction by subtraction of the blood .omega.3 polyunsaturated
fatty acid concentration before the administration of the
composition.
[0164] (6-4) A self-emulsifying composition, wherein, when the
self-emulsifying composition is orally administered to a human
before meals in an amount corresponding to 1800 mg of at least one
compound selected from the group consisting of .omega.3 PUFAs and
their pharmaceutically acceptable salts and esters, the maximum
blood .omega.3 PUFA concentration is at least 10 .mu.g/mL and/or
the area under the blood .omega.3 PUFA concentration vs time curve
from zero to 72 hours after the administration is at least 250
.mu.g/mLhr, as calculated with correction by subtraction of the
blood .omega.3 polyunsaturated fatty acid concentration before the
administration of the composition.
Advantageous Effects of Invention
[0165] The self-emulsifying composition of the present invention
contains a small amount of water instead of the ethanol and the
polyhydric alcohol in its composition. Compatibility of the
composition improves by such composition, and amount of the
emulsifier used can also be reduced, and accordingly, safety for
animals (including human) is thereby improved. In addition, the
.omega.3 PUFA will be included at a higher content, and this
enables reduction in the amount of emulsifier used, and compliance
is thereby improved.
[0166] Inclusion of the water in the composition also enables a
composition without or with minimized use of the ethanol or the
polyhydric alcohols, and hence, prevention of the softening of the
capsule film, and deformation of the capsule.
[0167] The self-emulsifying composition of the present invention is
excellent in at least one out of compatibility (appearance),
self-emulsifying property, composition dispersibility, emulsion
stability, and absorbability, and it will be rapidly absorbed even
if administered before meals or after the intake of low fat diet to
suppress the increase in serum TG after meals or, if administered
at bedtime, it will prevent the essential fatty acid deficiency in
a subject taking a lipase inhibitor.
[0168] In addition, the inventive self-emulsifying composition is
free from separation and cloudiness, that is to say, maintains good
appearance when stored at room temperature, a lower temperature
(e.g., 5.degree. C.) or a higher temperature (e.g., 40.degree. C.).
Preferably, the composition is free from separation and cloudiness
and thus maintains good appearance under any two out of the above
temperature conditions, more preferably under all three
conditions.
[0169] The self-emulsifying composition of the present invention
has at least one, preferably at least two, and more preferably all
of the advantageous characters as described above.
DESCRIPTION OF EMBODIMENTS
[0170] Next, the present invention is described in detail.
[0171] The present invention relates to a self-emulsifying
composition comprising 70 to 90% by weight in total of at least one
compound selected from the group consisting of .omega.3
polyunsaturated fatty acids and their pharmaceutically acceptable
salts and esters and 1 to 29% by weight of a particular emulsifying
agent and having low or no content of ethanol or polyhydric
alcohol, a capsulated self-emulsifying preparation having such
self-emulsifying composition encapsulated as a content, and a
pharmaceutical preparation, a production method and a method of use
thereof.
[0172] In the present invention, ".omega.3 PUFA" is a fatty acid
having a plurality of carbon--carbon double bonds in the molecule,
and the first double bond is at 3rd position from the end on the
side of the methyl group. Typical examples include
.alpha.-linolenic acid, EPA, DHA, eicosatrienoic acid, stearidonic
acid, eicosatetraenoic acid, clupanodonic acid, tetracosapentaenoic
acid, and nisinic acid. Unless otherwise specified, the terms
".omega.3 PUFA," "EPA," "DHA" and "fatty acid" as used in the
present invention mean a .omega.3 PUFA, EPA, DHA and a fatty acid
inclusive of pharmaceutically acceptable salts and esters thereof,
respectively.
[0173] The .omega.3 PUFA used in the present invention may be a
synthetic, semi-synthetic, natural .omega.3 PUFA, or a natural oil
containing such .omega.3 PUFA. Examples of the natural .omega.3
PUFA include an extract from a natural oil containing an .omega.3
PUFA, a crudely purified natural oil containing an .omega.3 PUFA,
and a highly purified natural oil containing an .omega.3 PUFA
produced by a method known in the art. Exemplary semi-synthetic
.omega.3 PUFAs include .omega.3 PUFAs produced by a microorganism
or the like and the .omega.3 PUFAs or the natural .omega.3 PUFAs
which have been subjected to a chemical treatment such as
esterification or ester exchange. In the present invention, the
.omega.3 PUFAs may be used alone or in combination of two or
more.
[0174] In the present invention, EPA and DHA are the preferable
examples of the .omega.3 PUFAs, and EPA is more preferable.
Examples of the pharmaceutically acceptable salts of the .omega.3
PUFA include inorganic salts such as sodium salts and potassium
salts, organic salts such as benzylamine salts and diethylamine
salts, salts with basic amino acids such as arginine salts and
lysine salts, and exemplary esters include alkyl esters such as
ethyl ester, and esters such as monoglyceride, diglyceride and
triglyceride. Preferable examples include ethyl ester and TG ester,
and the more preferred is ethyl ester. More specifically,
preferable examples include EPA-E, TG ester of EPA, DHA-E, and TG
ester of DHA, and among these, the more preferred are EPA-E and
DHA-E, and the most preferred is EPA-E.
[0175] The .omega.3 PUFA used as a starting material of the
self-emulsifying composition of the present invention is not
particularly limited in purity. The purity is typically such that
the content of the .omega.3 PUFA in relation to the total fatty
acid contained in the composition of the present invention could be
preferably at least 50% by weight, more preferably at least 70% by
weight, still more preferably at least 80% by weight, still more
preferably at least 90% by weight, still more preferably at least
96.5% by weight, and most preferably at least 98% by weight. The
.omega.3 PUFA containing EPA at a high purity, for example, the one
with an EPA content of at least 50% by weight is preferable, and
the content is more preferably at least 60% by weight, still more
preferably at least 70% by weight, still more preferably at least
80% by weight, still more preferably at least 90% by weight, even
more preferably at least 96.5% by weight, and most preferably at
least 98% by weight. In other words, the composition of the present
invention preferably has a high purity of .omega.3 PUFAs in the
total fatty acid, more preferably, a high purity of EPA+DHA as
.omega.3 PUFAs, and most preferably has EPA at such a purity that
EPA is essentially associated with no DHA or merely with, for
instance, less than 1.0%, preferably less than 0.5%, and more
preferably less than 0.2% of DHA.
[0176] For example, when EPA-E and DHA-E are used, compositional
ratio of EPA-E/DHA-E and content of (EPA-E+DHA-E) in relation to
the total fatty acid are not particularly limited as long as the
purity of EPA-E in the composition of the present invention is in
the range as described above. However, the compositional ratio of
the EPA-E/DHA-E is preferably at least 0.8, more preferably at
least 1.0, and most preferably at least 1.2.
[0177] The composition of the present invention may also contain a
polyunsaturated fatty acid other than the .omega.3 PUFA, such as
linoleic acid, .gamma. linolenic acid or dihomo-.gamma.-linolenic
acid, or a pharmaceutically acceptable salt or ester thereof. It,
however, is desirable that the content of arachidonic acid or a
pharmaceutically acceptable salt or ester thereof is low,
preferably less than 2% by weight, and more preferably less than 1%
by weight. Particularly preferred is the composition which is
essentially free from arachidonic acid and pharmaceutically
acceptable salts and esters thereof.
[0178] In the self-emulsifying composition of the present
invention, content of the .omega.3 PUFA is 70 to 90% by weight,
preferably 70 to 86% by weight, more preferably 72 to 85% by
weight, and still more preferably 74 to 84% by weight. The .omega.3
PUFA may be a single .omega.3 PUFA or a mixture of two or more
ones. If a mixture is used, the content of mixed fatty acids in the
self-emulsifying composition is 70 to 90% by weight in total.
[0179] The .omega.3 PUFA used may be a soft capsule containing the
EPA-E at a high purity (at least 96.5% by weight) (product name,
Epadel; manufactured by Mochida Pharmaceutical Co., Ltd.)
commercially available in Japan as a therapeutic agent for ASO and
hyperlipidemia or a high purity EPA-E containing capsule (product
name, VASCEPA; Amarin) commercially available in the U.S. as a
therapeutic agent for hypertriglyceridemia. The .omega.3 PUFA used
may also be a mixture of EPA-E and DHA-E, for example, Lovaza
(Registered Trademark) (a soft capsule containing about 46.5% by
weight of EPA-E and about 37.5% by weight of DHA-E from
GlaxoSmithKline) commercially available in the U.S. as a
therapeutic agent for hypertriglyceridemia or LOTRIGA (Registered
Trademark) (a soft capsule containing about 46.5% by weight of
EPA-E and about 37.5% by weight of DHA-E from Takeda Pharmaceutical
Co., Ltd.) commercially available in Japan. It is also possible to
use a mixture of EPA and DHA such as Epanova (Registered Trademark)
(a soft capsule containing about 50 to 60% by weight of EPA free
acid and about 15 to 25% by weight of DHA free acid from
AstraZeneca) commercially available in the U.S. as a therapeutic
agent for hypertriglyceridemia.
[0180] Purified fish oils may also be used for the .omega.3 PUFA,
and uses of monoglyceride(MG), diglyceride(DG), and TG derivatives
and combinations thereof as the .omega.3 PUFA are also preferable
embodiments. Various products containing the .omega.3 PUFA are
commercially available, for example, Incromega F2250, F2628, E2251,
F2573, TG2162, TG2779, TG2928, TG3525, and E5015 (Croda
International PLC, Yorkshire, England), and EPAX6000FA, EPAX5000TG,
EPAX4510TG, EPAX2050TQ EPAX7010EE, K85TG, K85EE, and K80EE (Pronova
Biopharma, Lysaker, Norway). These products may be purchased and
used for the composition of the present invention.
[0181] In the present invention, the "polyoxyethylene sorbitan
fatty acid ester" is polyoxyethylene ether of a fatty acid ester
wherein a part of the hydroxy groups of anhydrous sorbitol have
been esterified with a fatty acid. Various compounds with different
esterifying fatty acids are commercially available, and examples
include polyoxyethylene (20) sorbitan monolaurate (NIKKOL TL-10,
polysorbate 20, Tween 20), polyoxyethylene (20) sorbitan
monopalmitate (NIKKOL TP-10V, Polysorbate 40, Tween 40),
polyoxyethylene (20) sorbitan monostearate (NIKKOL TS-10MV,
polysorbate 60, Tween 60), polyoxyethylene (20) sorbitan
tristearate (NIKKOL TS-30V, polysorbate 65), polyoxyethylene (20)
sorbitan monoisostearate (NIKKOL TI-10V), polyoxyethylene (20)
sorbitan monooleate (NIKKOL TO-10MV, polysorbate 80, Tween 80), and
polyoxyethylene (20) sorbitan trioleate (NIKKOL TO-30V, polysorbate
85), and the preferred are polyoxyethylene (20) sorbitan
monostearate, polyoxyethylene (20) sorbitan monooleate, and
polyoxyethylene (20) sorbitan trioleate, and the more preferred is
polyoxyethylene (20) sorbitan monooleate.
[0182] These may be used alone or in combination of two or more.
The term "polyoxyethylene sorbitan fatty acid ester" as used in the
present invention means all of such compounds.
[0183] Content of the polyoxyethylene sorbitan fatty acid ester in
the self-emulsifying composition of the present invention is not
particularly limited as long as the merits of the present invention
are not adversely affected. The content is generally 1 to 29% by
weight, preferably 5 to 20% by weight, and more preferably 7 to 15%
by weight when the self-emulsifying composition is defined to be
100% by weight as a whole.
[0184] In the present invention, the "sorbitan fatty acid ester" is
a compound obtained by esterifying hydroxy groups of anhydrous
sorbitol with a fatty acid. Various compounds with different
esterifying fatty acids are commercially available, and examples
include sorbitan monolaurate (Span 20; NIKKOL SL-10; Nonion
LP-20R), sorbitan monostearate (NIKKOL SS-10MV), sorbitan
monooleate (Span 80; NIKKOL SO-10V), sorbitan monopalmitate (Span
40; NIKKOL SP-10V), sorbitan trioleate (NIKKOL SO-30) and sorbitan
sesquioleate (Span 83; NIKKOL SO-15MV; Nonion OP-83R), with
sorbitan monolaurate, sorbitan monooleate and sorbitan
sesquioleate, among orhers sorbitan monolaurate, being preferred.
These may be used alone or in combination of two or more. The term
"sorbitan fatty acid ester" as used in the present invention means
all of such compounds.
[0185] Content of the sorbitan fatty acid ester in the
self-emulsifying composition of the present invention is not
particularly limited as long as the merits of the present invention
are not adversely affected. The content is generally 1 to 20% by
weight, preferably 2 to 15% by weight, and more preferably 3 to 10%
by weight when the self-emulsifying composition is defined to be
100% by weight as a whole, or 2 to 8% by weight, preferably 2 to 7%
by weight, and more preferably 3 to 5% by weight when the
self-emulsifying composition is defined to be 100% by weight as a
whole.
[0186] In the present invention, the "glycerin fatty acid ester" is
an ester of a fatty acid and glycerin or polyglycerin and
derivatives thereof (including glycerin fatty acid ester, acetic
and fatty acid esters of glycerol, lactic and fatty acid esters of
glycerol, citric and fatty acid esters of glycerol, succinic and
fatty acid esters of glycerol, diacetyl tartaric and fatty acid
esters of glycerol, glycerin acetic acid ester, polyglycrin fatty
acid ester, and polygrycelin condensed ricinoleic acid ester).
[0187] Various compounds are commercially available, and examples
include glyceryl monooleate (PECEOL), glyceryl monostearate (NIKKOL
MGS-F50SEV, MGS-AMV, MGS-BMV), decaglyceryl monooleate (NIKKOL
Decaglyn 1-OV; POEM J-0381V), decaglyceryl monolaurate (NIKKOL
Decaglyn 1-L), dacaglyceryl trioleate (NIKKOL Decaglyn 3-OV),
decaglyceryl pentaoleate (NIKKOL Decaglyn 5-OV) and tetraglyceryl
monooleate (NIKKOL Tetraglyn 1-OV), with glyceryl monooleate,
decaglyceryl monooleate and glyceryl monostearate, among others
decaglyceryl monooleate, being preferred. These may be used alone
or in combination of two or more. The term "glycerin fatty acid
ester" as used in the present invention means all of such
compounds.
[0188] Content of the glycerin fatty acid ester in the
self-emulsifying composition of the present invention is not
particularly limited as long as the merits of the present invention
are not adversely affected. The content is generally 1 to 25% by
weight, preferably 3 to 20% by weight, more preferably 5 to 15% by
weight, and even more preferably 6 to 10% by weight when the
self-emulsifying composition is defined to be 100% by weight as a
whole, or 1 to 20% by weight, preferably 1 to 15% by weight, more
preferably 1 to 10% by weight, and even more preferably 1 to 8% by
weight when the self-emulsifying composition is defined to be 100%
by weight as a whole.
[0189] In the present invention, the "polyoxyethylene castor oil"
is a compound prepared by addition polymerization of ethylene oxide
to castor oil. Various compounds with different average degrees of
polymerization of ethylene oxide are commercially available, and
examples include NIKKOL CO-3 (Nikko Chemicals Co., Ltd.) with an
average ethylene oxide mole number of 3, NIKKOL CO-10 (Nikko
Chemicals Co., Ltd.) with an average ethylene oxide mole number of
10, EMALEX C-20 (Nippon Emulsion Co., Ltd.) with an average
ethylene oxide mole number of 20, EMALEX C-30 (Nippon Emulsion Co.,
Ltd.) with an average ethylene oxide mole number of 30, Kolliphor
EL (BASF) (polyoxyl 35 castor oil) with an average ethylene oxide
mole number of 35, EMALEX C-40 (Nippon Emulsion Co., Ltd.) with an
average ethylene oxide mole number of 40, and EMALEX C-50 (Nippon
Emulsion Co., Ltd.) with an average ethylene oxide mole number of
50, and the preferred is Kolliphor EL. These may be used alone or
in combination of two or more. The term "polyoxyethylene castor
oil" as used in the present invention means all of such compounds
unless otherwise noted.
[0190] Content of the polyoxyethylene castor oil in the
self-emulsifying composition of the present invention is not
particularly limited as long as the merits of the present invention
are not adversely affected. The content is generally 1 to 20% by
weight, preferably 2 to 15% by weight, more preferably 3 to 10% by
weight, and even more preferably 4 to 6% by weight when the
self-emulsifying composition is defined to be 100% by weight as a
whole.
[0191] Preferred embodiments of the self-emulsifying composition of
the invention are as described in the following i) and/or ii).
[0192] i) A preferred embodiment of the inventive self-emulsifying
composition contains at least a polyoxyethylene sorbitan fatty acid
ester as an emulsifier. More preferably, the inventive composition
contains a polyoxyethylene sorbitan fatty acid ester as a chief
emulsifier. In another preferred embodiment, the emulsifying agent
to be used for the composition is essentially composed of a
polyoxyethylene sorbitan fatty acid ester and at least one selected
from among a sorbitan fatty acid ester, a glycerin fatty acid ester
and a polyoxyethylene castor oil.
[0193] The amount of a polyoxyethylene sorbitan fatty acid ester
contained as a chief emulsifier will be at least 40 parts by
weight, preferably at least 50 parts by weight, and more preferably
at least 60 parts by weight when the total amount of emulsifiers
contained in the composition is defined as 100 parts by weight. The
amount of at least one emulsifier selected from among a sorbitan
fatty acid ester, a glycerin fatty acid ester and a polyoxyethylene
castor oil and used in combination with the polyoxyethylene
sorbitan fatty acid ester will be up to 60 parts by weight,
preferably up to 50 parts by weight, and more preferably up to 40
parts by weight when the total amount of the emulsifying agent to
be used for the composition is defined as 100 parts by weight.
[0194] ii) Still another preferred embodiment of the inventive
self-emulsifying composition contains at least two selected from
among a sorbitan fatty acid ester, a glycerin fatty acid ester and
a polyoxyethylene castor oil. This embodiment may not contain a
polyoxyethylene sorbitan fatty acid ester.
[0195] While the combination of two emulsifiers is not particularly
limited, preferred are combinations of a sorbitan fatty acid ester
and a polyoxyethylene castor oil, of a glycerin fatty acid ester
and a polyoxyethylene castor oil, and of a sorbitan fatty acid
ester and a glycerin fatty acid ester, with a combination of a
sorbitan fatty acid ester and a polyoxyethylene castor oil and a
combination of a glycerin fatty acid ester and a polyoxyethylene
castor oil being more preferred.
[0196] In this embodiment, the amount of an emulsifier contained in
the composition in a larger amount than any other emulsifier is
preferably up to 75 parts by weight, more preferably up to 67 parts
by weight, and even more preferably up to 60 parts by weight when
the total amount of emulsifiers contained in the composition is
defined as 100 parts by weight. In some cases, the amount of such
emulsifier is preferably 30 to 80 parts by weight, more preferably
35 to 70 parts by weight, even more preferably 38 to 67 parts by
weight, and most preferably 40 to 55 parts by weight.
[0197] In the self-emulsifying composition of the present
invention, a plurality of emulsifiers including a polyoxyethylene
castor oil may be used as an emulsifying agent. The amount of
polyoxyethylene castor oil contained in the composition is
preferably up to 70 parts by weight, more preferably up to 60 parts
by weight, and even more preferably up to 50 parts by weight when
the total amount of emulsifiers contained in the composition is
defined as 100 parts by weight. In some cases, the amount of
polyoxyethylene castor oil is preferably 10 to 70 parts by weight,
more preferably 15 to 60 parts by weight, even more preferably 17
to 40 parts by weight, and most preferably 18 to 30 parts by
weight.
[0198] The self-emulsifying composition of the present invention
may also contain an emulsifier other than the polyoxyethylene
sorbitan fatty acid ester, sorbitan fatty acid ester, glycerin
fatty acid ester and polyoxyethylene castor oil, while the amount
of such an emulsifier is up to 20 parts by weight, preferably up to
10 parts by weight, more preferably up to 5 parts by weight, and
most preferably none when the total amount of emulsifiers used for
the composition is defined as 100 parts by weight. The additional
emulsifier is not particularly limited as long as it satisfies at
least one of the demands as described above, and exemplary
additional emulsifiers include polyoxyethylene hydrogenated castor
oil, propylene glycol fatty acid ester, saturated polyglycolated
glyceride, polyoxyethylene polypropylene glycol, and sucrose fatty
acid ester.
[0199] The total content of emulsifiers in the self-emulsifying
composition of the present invention is not particularly limited as
long as the merits of the present invention are not adversely
affected. The total emulsifier content is generally 1 to 29% by
weight, preferably 5 to 29% by weight, more preferably 6 to 29% by
weight, still more preferably 7 to 29% by weight, and even more
preferably 8 to 29% by weight, especially 9 to 29% by weight, when
the self-emulsifying composition is defined to be 100% by weight as
a whole. In some cases, the total emulsifier content is preferably
5 to 24% by weight, and more preferably 10 to 20% by weight. In
alternative cases, the total emulsifier content is preferably 6 to
28% by weight, more preferably 8 to 26% by weight, and even more
preferably 9 to 25% by weight. In addition, the total amount of
emulsifiers contained in the composition is 5 to 45 parts by
weight, preferably 10 to 45 parts by weight, more preferably 15 to
35 parts by weight, and even more preferably 15 to 20 parts by
weight in relation to 100 parts by weight of the .omega.3 PUFA.
[0200] The composition and the pharmaceutical preparation of the
present invention contain a small amount of water. Addition of
water to a composition containing a hydrophobic lipid is generally
conceived as a loss of compatibility. Presence of a specified
amount of water in the inventive composition results in an improved
compatibility of the composition, makes the use of a polyhydric
alcohol and ethanol unnecessary, and thus allows the product which
has a transparent appearance and gets rid of the problem of
separation or cloudiness of a composition, even though not
containing a polyhydric alcohol, ethanol or lecithin.
[0201] A small amount of water may be added during the preparation
of the self-emulsifying composition, or the water in the gelatin
capsule film may transfer to the self-emulsifying composition after
the encapsulation of the self-emulsifying composition in the
capsule.
[0202] In addition, the composition free from the polyhydric
alcohol and the ethanol does not cause the capsule to be softened
or deformed after the encapsulation, nor has side effects of the
ethanol on alcohol intolerance patients taking the composition.
[0203] The water content of the self-emulsifying composition is
preferably 0.5 to 6% by weight, more preferably 0.5 to 4% by
weight, still more preferably 0.5 to 3% by weight, and even more
preferably 0.5 to 2.5% by weight, with a content of 0.7 to 1.5% by
weight being most preferred, when the composition is defined to be
100% by weight as a whole.
[0204] The water content is preferably 1 to 30% by weight, more
preferably 2 to 25% by weight, still more preferably 3 to 20% by
weight, and even more preferably 4 to 15% by weight, with a content
of 5 to 9% by weight being most preferred, when the total amount of
emulsifiers contained in the self-emulsifying composition is
defined as 100 parts by weight.
[0205] In the present invention, the "lecithin" is a type of
glycerophospholipid, and examples include soybean lecithin,
zymolytic soybean lecithin, hydrogenated soybean lecithin, egg yolk
lecithin, hydrogenated phospholipid, phospholipid from milk,
lysolecithin, phosphatidyl choline, and phosphatidyl serine. The
preferred are soybean lecithin, zymolytic soybean lecithin,
hydrogenated soybean lecithin, and egg yolk lecithin, and the more
preferred is soybean lecithin. These may be used alone or in
combination of two or more. The term "lecithin" as used in the
present invention means all of such glycerophospholipids unless
otherwise noted. In the present invention, lecithin is not included
in the emulsifying agent.
[0206] Various lecithins are commercially available, and exemplary
such products include purified soybean lecithin (Nisshin Oilio),
purified egg yolk lecithin (Asahi Kasei Pharma Corporation), and
egg yolk lecithin PL-100M (Kewpie Corporation), and use of such
products is also possible. Exemplary soybean lecithins include
BASIS LP-20B (Nisshin Oil Mills, Ltd.) and Lipoid S45 and S20
(Lipoid), and exemplary zymolytic lecithins include BASIS LP-20E
(Nisshin Oil Mills, Ltd.) and Phospholipon RLPC20 (Lipoid). Various
such commercially available products may be used in the
composition.
[0207] In a preferred embodiment of the self-emulsifying
composition of the present invention, essentially no lecithin is
contained. For instance, 3 or more parts by weight of lecithin is
not contained in the composition in relation to 100 parts by weight
of the .omega.3 PUFA. In other words, the amount of lecithin
contained in the composition is less than 3 parts by weight,
preferably less than 2 parts by weight, more preferably less than 1
part by weight, and most preferably 0 parts by weight. The amount
of lecithin contained in the inventive self-emulsifying composition
is preferably 0 parts by weight or more but less than 3 parts by
weight, and more preferably 0 parts by weight or more but less than
1 part by weight.
[0208] The lecithin content is preferably lower than 2.1% by
weight, more preferably lower than 1.4% by weight, and even more
preferably lower than 0.7% by weight when the self-emulsifying
composition is defined to be 100% by weight as a whole.
[0209] In the present invention, the "polyhydric alcohol" is a
polyol compound having the structure of a straight chain or cyclic
aliphatic hydrocarbon wherein two or more carbon atoms are each
substituted with one hydroxy group. Exemplary such polyhydric
alcohols include divalent alcohols such as ethylene glycol,
propylene glycol, trimethylene glycol, 1,2-butylene glycol,
tetramethylene glycol, 1,3-butylene glycol, 2,3-butylene glycol,
and pentamethylene glycol; trivalent alcohols such as glycerin,
trimethylolpropane, and 1,2,6-hexane triol; and polyhydric alcohol
polymers such as diethylene glycol, dipropylene glycol triethylene
glycol, polyethylene glycol, polypropylene glycol, and
polyglycerin, and the preferred is propylene glycol or glycerin.
The glycerin also includes concentrated glycerin. The term
"polyhydric alcohol" as used in the present invention means all of
such polyol compounds unless otherwise noted.
[0210] Advantageously, the content of the polyhydric alcohol in the
self-emulsifying composition of the present invention is such that
it does not cause a capsule filled with the composition to be
deformed. In a preferred embodiment, the inventive composition
contains essentially no polyhydric alcohol. In other words, the
composition does not contain the polyhydric alcohol at a content
higher than 4% by weight, for instance, when the composition is
defined to be 100% by weight as a whole. Alternatively, the
polyhydric alcohol content is up to 4% by weight, preferably up to
3% by weight, more preferably up to 2% by weight, even more
preferably up to 1% by weight, and most preferably 0% by
weight.
[0211] Advantageously, the content of the ethanol in the
self-emulsifying composition of the present invention is such that
change in the quality is not induced during the encapsulation,
distribution or storage, and denaturing of the capsule content is
not induced either, and the ethanol content should not exceed the
daily experientially allowable medical dose. In a preferred
embodiment, the inventive composition contains essentially no
ethanol. In other words, the composition does not contain the
ethanol at a content higher than 4% by weight, for instance, when
the composition is defined to be 100% by weight as a whole.
Alternatively, the ethanol content is up to 4% by weight,
preferably up to 3% by weight, more preferably up to 2% by weight,
even more preferably up to 1% by weight, and most preferably 0% by
weight.
[0212] When the ethanol and the polyhydric alcohol are added in the
composition, the total content of the ethanol and the polyhydric
alcohol is preferably not more than 4% by weight when the
composition is defined to be 100% by weight as a whole. The total
content of the ethanol and the polyhydric alcohol in the
composition is preferably up to 4% by weight, more preferably up to
3% by weight, still more preferably up to 2% by weight, even more
preferably up to 1% by weight, and most preferably 0% by
weight.
[0213] Preferable ethanol concentration may be determined based on
the .omega.3 PUFA concentration of the self-emulsifying composition
and the daily dose of the self-emulsifying composition. When the
self-emulsifying composition of the present invention is orally
administered at a daily dose of 1800 mg in terms of .omega.3 PUFA,
and a preparation containing the .omega.3 PUFA, for example, at 75%
by weight is prepared, the ethanol dose will not exceed 3.26 mg
which is daily maximum dose described in the "Dictionary of
Pharmaceutical Additives" when the ethanol concentration is up to
0.135% by weight.
[0214] For the self-emulsifying composition of the present
invention containing such .omega.3 PUFA and emulsifying agent as
described above, a preferred embodiment is the combination
containing 1) EPA-E and/or DHA-E, 2) water, and 3) a
polyoxyethylene sorbitan fatty acid ester as an emulsifier. Another
preferred embodiment is the combination of 1) EPA-E and/or DHA-E,
2) water, and 3) at least two emulsifiers selected from the group
consisting of a sorbitan fatty acid ester, a glycerin fatty acid
ester and a polyoxyethylene castor oil.
[0215] Another preferred embodiment is the combination of 1) EPA-E
and/or DHA-E, 2) water, 3) a polyoxyethylene sorbitan fatty acid
ester as an emulsifier, and 4) at least one emulsifier selected
from the group consisting of a sorbitan fatty acid ester, a
glycerin fatty acid ester and a polyoxyethylene castor oil. Yet
another preferred embodiment is the combination of 1) EPA-E and/or
DHA-E, 2) water, 3) a polyoxyethylene sorbitan fatty acid ester as
an emulsifier, and 4) at least two emulsifiers selected from the
group consisting of a sorbitan fatty acid ester, a glycerin fatty
acid ester and a polyoxyethylene castor oil.
[0216] In each of such self-emulsifying compositions, the content
of the EPA-E and/or DHA-E 1) is 70 to 90% by weight, the content of
the water 2) is 0.5 to 6% by weight, and the content of the
emulsifier or emulsifiers 3) is 1 to 29% by weight when the
relevant composition is defined to be 100% by weight as a
whole.
[0217] The self-emulsifying composition of the present invention
may be encapsulated in a capsule. The capsule selected may be a
hard capsule or a soft capsule, and preferably, the capsule used is
a soft capsule. The soft capsule is not particularly limited in
shape, and preferably, the soft capsule is a rotary die type soft
capsule or a seamless capsule.
[0218] In the soft capsule of the present invention, the capsule
film is not necessarily limited for its composition, and exemplary
main ingredients include gelatin, carageenan, pectin, pullulan,
sodium arginate, starch, hypromellose, hydroxypropyl cellulose, and
other known ingredients. The preferred is gelatin, and the type of
gelatin used is not particularly limited. Exemplary gelatins
include acid-treated gelatin, alkali-treated gelatin, amphoteric
gelatin, chemically modified gelatin, and other known gelatins,
which may be used alone or in combination of two or more. The
gelatin used is preferably an acid-treated gelatin or
alkali-treated gelatin. The source of the gelatin is not
necessarily limited, and the gelatin used may be the one from
cattle bone, cattle skin, pig bone, pig skin, fish scale, or fish
skin, and preferably, the one from cattle bone, cattle skin, pig
bone, or pig skin.
[0219] The "gelatin" used may be the one normally used in the
production of a soft capsule, for example, medical gelatin (gelatin
and purified gelatin) defined in The Japanese Pharmacopoeia 16th
edition. The gelatin may also be a combination of two or more
types, and the capsule film may also contain other components such
as a plasticizing agent.
[0220] The "plasticizing agent" added to the capsule film may be
the one normally used in the production of a soft capsule, with
preferred examples including a polyhydric alcohol such as glycerin
(for example, concentrated glycerin), ethylene glycol, polyethylene
glycol, propylene glycol, or polypropylene glycol, and a sugar
alcohol such as sorbitol, mannitol, or xylitol. These plasticizing
agents may be used in combination of two or more. Particularly
preferred are glycerin and sorbitol. Also preferred is a
combination of glycerin and sorbitol, and in this case, the
glycerin and the sorbitol may be used at a weight ratio in the
range of 1:5 to 5:1, and more preferably 1:3 to 3:1.
[0221] In the soft capsule preparation, and in particular, in the
seamless capsule of the present invention, the capsule film
solution preferably contains the gelatin and the plasticizing agent
at a weight ratio in the range of 10:1 to 1:10, and more preferably
of 10:1 to 1:1.
[0222] The weight ratio between the capsule film solution and the
capsule content is typically 10:1 to 1:10, and preferably 3:1 to
1:10.
[0223] If desired, the capsule film may also contain various
additives commonly used in the capsule film. Exemplary such
additives include amino acids, citric acid, glycerin, sorbitol,
trehalose, and other plasticizing agents, antiseptic, dye, titanium
oxide, and other colorants, and organic acids.
[0224] The composition for the capsule film may be prepared by
dissolving gelatin, the plasticizing agent, and the optional
additives in water at room temperature or at an elevated
temperature.
[0225] A capsulated self-emulsifying preparation having the
self-emulsifying composition of the present invention as its liquid
content preferably has high hardness immediately after the
production, and this hardness is preferably maintained during the
storage. Loss of the hardness is unfavorable in view of the quality
because the loss of the hardness does not only result in the
deformation but also fragileness and breakage of the capsule and
bleeding of the content. Softening of the capsule can be detected
by measuring the hardness with a common hardness tester.
[0226] The capsulated self-emulsifying preparation of the present
invention has the hardness immediately after the production of at
least 18 kgf, preferably at least 20 kgf, and more preferably at
least 22 kgf. It is desirable that the hardness of the preparation
does not substantially decrease, or not decrease by 6 kgf or more
when the preparation is stored in a tightly sealed aluminum package
at 40.degree. C. for 1 week compared with the hardness immediately
after the production. Preferably, the inventive preparation has a
hardness of at least 10 kgf, more preferably of at least 15 kgf,
and even more preferably of at least 20 kgf after the storage at
40.degree. C. for 1 week.
[0227] With the hardness immediately after the production being
assumed to be 100%, at least 60%, preferably at least 70%, more
preferably at least 80%, and most preferably at least 90% thereof
is exhibited (maintained) after the storage in a tightly sealed
aluminum package at 40.degree. C. for 1 week.
[0228] The dose and dosage period of the .omega.3 PUFA used in the
self-emulsifying composition of the present invention are made
sufficient for realizing the intended action, and can be adequately
adjusted depending on the administration route, frequency of
administration per day, seriousness of the symptoms, body weight,
age, and other factors.
[0229] In the case of oral administration, the composition is
administered one to three times a day at an EPA-E dose, for
instance, of 0.1 to 5 g/day, preferably of 0.2 to 3 g/day, more
preferably of 0.3 to 3 g/day, still more preferably of 0.5 to 3
g/day, and even more preferably of 0.9 to 3 g/day. The
administration may be conducted one time at the entire dose or
several times at divided doses as required. The frequency of
administration per day is preferably one time a day or two or three
times a day. In the case of one time administration per day, one to
ten capsules, preferably one to eight capsules, more preferably one
to six capsules, still more preferably one to four capsules, and
even more preferably one to three capsules as soft capsules each
containing 1 g of EPA-E, for instance, can be administered. Soft
capsules each containing 1 g of EPA-E may be combined with soft
capsules each containing 0.5 g of the ester so as to administer the
composition at an EPA-E dose of 0.5 g, 1.5 g, 2.5 g, 3.5 g, 4.5 g
or 5.5 g/administration.
[0230] While administration of EPA-E during to after meals is
deemed preferable, and administration immediately after meals
(within 30 minutes after meals) more preferable, because the
absorption of EPA-E is influenced by diet, the self-emulsifying
composition of the present invention has an excellent absorbability
under fasting, and therefore, it exerts the intended effects even
when administered at a timing other than during, after or
immediately after meals, for example, before or immediately before
meals, between meals, or at bedtime; when administered to patients
with reduced absorption ability of the intestinal tract (for
example, elderly, patients of intestinal disease, patients after
intestinal surgery, terminal cancer patients, or patients taking a
lipase inhibitor); or when administered at a reduced dose.
[0231] The self-emulsifying composition of the present invention is
preferably characterized in that the time until the maximum blood
concentration is attained after the oral administration is
comparable to or shorter than that found for the .omega.3 PUFA
stock solution. Otherwise, the inventive composition is preferably
characterized in that the maximum blood concentration is higher
than that found for the .omega.3 PUFA stock solution. In addition,
the inventive composition is preferably characterized in that the
blood concentration two hours after the administration, the area
under the blood concentration vs time curve from zero to two hours
after the administration, and/or the area under the blood
concentration vs time curve from zero to 72 hours after the
administration is comparable to or higher than that found for the
.omega.3 PUFA stock solution. More preferably, the self-emulsifying
composition of the present invention is characterized in that the
time until the maximum blood concentration is attained is short,
the maximum blood concentration is high, and both the blood
concentration two hours after the administration and the area under
the blood concentration vs time curve from zero to two hours and/or
from zero to 72 hours after the administration are high as compared
with those for the .omega.3 PUFA stock solution, respectively.
[0232] Such pharmacokinetics as above can be confirmed with dogs,
monkeys or other animals, and preferably by examination on
humans.
[0233] In a pharmacokinetic study conducted by orally administering
the self-emulsifying composition to male beagles as fasted for at
least 18 hours at an .omega.3 PUFA dose of 600 mg, the maximum
.omega.3 PUFA blood concentration is, for instance, preferably at
least 50 .mu.g/mL, more preferably at least 60 .mu.g/mL, and even
more preferably at least 70 .mu.g/mL, as calculated with correction
by subtraction of the blood .omega.3 polyunsaturated fatty acid
concentration before the administration of the composition. The
area under the blood .omega.3 PUFA concentration vs time curve from
zero to two hours after the administration is preferably at least
50 .mu.g/mLhr, more preferably at least 60 .mu.g/mLhr, and even
more preferably at least 70 .mu.g/mLhr. The combination of the
ranges of the maximum .omega.3 PUFA blood concentration and the
area under the blood .omega.3 PUFA concentration vs time curve is
preferably a combination of the range of at least 50 .mu.g/mL and
the range of at least 50 .mu.g/mLhr, more preferably a combination
of the range of at least 60 .mu.g/mL and the range of at least 60
.mu.g/mLhr, and even more preferably a combination of the range of
at least 70 .mu.g/mL and the range of at least 70 .mu.g/mLhr.
[0234] In a pharmacokinetic study conducted by orally administering
the self-emulsifying composition to male crab-eating macaques as
fasted for at least 12 hours at an .omega.3 PUFA dose of 45 mg/kg
body weight, the maximum .omega.3 PUFA blood concentration is
preferably at least 50 .mu.g/mL, and more preferably at least 70
.mu.g/mL, as calculated with correction by subtraction of the blood
.omega.3 polyunsaturated fatty acid concentration before the
administration of the composition. The area under the blood
.omega.3 PUFA concentration vs time curve from zero to 12 hours
after the administration is preferably at least 400 .mu.g/mLhr, and
more preferably at least 500 .mu.g/mL. The combination of the
ranges of the maximum .omega.3 PUFA blood concentration and the
area under the blood .omega.3 PUFA concentration vs time curve as
above is preferably a combination of the range of at least 50
.mu.g/mL and the range of at least 400 .mu.g/mLhr, and more
preferably a combination of the range of at least 70 .mu.g/mL and
the range of at least 500 .mu.g/mLhr.
[0235] In a pharmacokinetic study conducted by orally administering
the self-emulsifying composition to humans at such a timing as
before meals, immediately after meals or after meals at an .omega.3
PUFA or EPA dose of 1800 mg, the maximum .omega.3 PUFA blood
concentration is preferably at least 50 .mu.g/mL, more preferably
at least 100 .mu.g/mL, still more preferably at least 150 .mu.g/mL,
even more preferably at least 200 .mu.g/mL, and most preferably at
least 300 .mu.g/mL, as calculated with correction by subtraction of
the blood .omega.3 polyunsaturated fatty acid concentration before
the administration of the composition. Alternatively, the maximum
.omega.3 PUFA blood concentration is preferably 10 to 1000
.mu.g/mL, more preferably 20 to 500 .mu.g/mL, still more preferably
40 to 300 .mu.g/mL, even more preferably 50 to 150 .mu.g/mL, and
most preferably 50 to 100 .mu.g/mL. The area under the blood
.omega.3 PUFA concentration vs time curve from zero to 72 hours
after the administration is preferably at least 500 .mu.g/mLhr,
more preferably at least 1000 .mu.g/mLhr, still more preferably at
least 1500 .mu.g/mLhr, even more preferably at least 2000
.mu.g/mLhr, and most preferably at least 3000 .mu.g/mLhr.
Alternatively, the area under the blood .omega.3 PUFA concentration
vs time curve as above is preferably 500 to 4500 .mu.g/mLhr, more
preferably 600 to 3000 .mu.g/mLhr, still more preferably 700 to
2500 .mu.g/mLhr, even more preferably 800 to 2000 .mu.g/mLhr, and
most preferably 1000 to 1500 .mu.g/mLhr. The time until the maximum
plasma concentration is attained is preferably up to 6 hours, more
preferably up to 5 hours, still more preferably up to 3 hours, even
more preferably up to 1 hour, and most preferably less than one
hour. Alternatively, the time until the maximum plasma
concentration is attained is preferably 0.5 to 10 hours, more
preferably 1 to 8 hours, still more preferably 1.5 to 7 hours, even
more preferably 2 to 5 hours, and most preferably 2.5 to 4 hours.
The plasma elimination half-life is preferably at least 10 hours,
more preferably at least 20 hours, still more preferably at least
30 hours, even more preferably at least 40 hours, and most
preferably at least 50 hours. Alternatively, the plasma elimination
half-life is preferably 0 to 150 hours, more preferably 10 to 120
hours, still more preferably 30 to 100 hours, even more preferably
25 to 75 hours, and most preferably 25 to 50 hours.
[0236] In a pharmacokinetic study conducted by orally administering
the self-emulsifying composition to humans at such a timing as
before meals, immediately after meals or after meals at an .omega.3
PUFA or EPA dose of 3600 mg, the maximum .omega.3 PUFA blood
concentration is preferably at least 50 .mu.g/mL, more preferably
at least 100 .mu.g/mL, still more preferably at least 150 .mu.g/mL,
even more preferably at least 200 .mu.g/mL, and most preferably at
least 300 .mu.g/mL, as calculated with correction by subtraction of
the blood .omega.3 polyunsaturated fatty acid concentration before
the administration of the composition. Alternatively, the maximum
.omega.3 PUFA blood concentration is preferably 10 to 1000
.mu.g/mL, more preferably 20 to 500 .mu.g/mL, still more preferably
50 to 400 .mu.g/mL, even more preferably 100 to 300 .mu.g/mL, and
most preferably 150 to 200 .mu.g/mL. The area under the blood
.omega.3 PUFA concentration vs time curve from zero to 72 hours
after the administration is preferably at least 500 .mu.g/mLhr,
more preferably at least 1000 .mu.g/mLhr, still more preferably at
least 1500 .mu.g/mLhr, even more preferably at least 2000
.mu.g/mLhr, and most preferably at least 3000 .mu.g/mLhr.
Alternatively, the area under the blood .omega.3 PUFA concentration
vs time curve as above is preferably 500 to 5000 .mu.g/mLhr, more
preferably 1000 to 4700 .mu.g/mLhr, still more preferably 1500 to
4500 .mu.g/mLhr, even more preferably 2000 to 4000 .mu.g/mLhr, and
most preferably 2500 to 3500 .mu.g/mLhr. The time until the maximum
plasma concentration is attained is preferably up to 6 hours, more
preferably up to 5 hours, still more preferably up to 3 hours, even
more preferably up to 1 hour, and most preferably less than one
hour. Alternatively, the time until the maximum plasma
concentration is attained is preferably 0.5 to 10 hours, more
preferably 1 to 8 hours, still more preferably 1.5 to 7 hours, even
more preferably 2 to 6 hours, and most preferably 3 to 5 hours. The
plasma elimination half-life is preferably at least 10 hours, more
preferably at least 20 hours, still more preferably at least 30
hours, even more preferably at least 40 hours, and most preferably
at least 50 hours. Alternatively, the plasma elimination half-life
is preferably 0 to 150 hours, more preferably 10 to 120 hours,
still more preferably 30 to 100 hours, even more preferably 25 to
75 hours, and most preferably 25 to 50 hours.
[0237] In the case of a pharmacokinetic study with humans, the
above-mentioned numerical ranges may also be replaced by those
mentioned below. To be more specific: In a study conducted by
orally administering the self-emulsifying composition at such a
timing as before, immediately after or after meals at an EPA dose
of 1800 mg, the maximum .omega.3 PUFA plasma concentration as
calculated with correction by subtraction of the blood .omega.3
polyunsaturated fatty acid concentration before the administration
of the composition is not particularly limited, while it may be
specified to be: 10 to 50; 50 to 100; 100 to 150; 150 to 200; 200
to 250; 250 to 300; 300 to 350; 350 to 400; 400 to 450; 450 to 500;
500 to 600; 600 to 700; 700 to 800; 800 to 900; 900 to 1000; 10 to
30; 20 to 40; 30 to 50; 40 to 60; 50 to 70; 60 to 80; 70 to 90; 80
to 100; 90 to 110; 100 to 120; 110 to 130; 120 to 140; 130 to 150;
140 to 160; 150 to 170; 160 to 180; 170 to 190; 180 to 200; 190 to
210; 200 to 220; 220 to 240; 240 to 260; 260 to 280; 280 to 300; 10
to 20; 15 to 25; 20 to 30; 25 to 35; 30 to 40; 35 to 45; 40 to 50;
45 to 55; 50 to 55; 53 to 58; 55 to 60; 58 to 63; 60 to 65; 63 to
68; 65 to 70; 68 to 73; 70 to 75; 73 to 78; 75 to 80; 78 to 83; 80
to 85; 83 to 88; 85 to 90; 88 to 93; 90 to 95; 93 to 98; 95 to 100;
98 to 103; 100 to 105; 103 to 108; 105 to 110; 108 to 113; 110 to
115; 113 to 118; 115 to 120; 118 to 123; 120 to 125; 123 to 128;
125 to 130; 128 to 133; 130 to 135; 133 to 138; 135 to 140; 138 to
143; 140 to 145; 143 to 148; 145 to 150; 150 to 160; 155 to 165;
160 to 170; 165 to 175; 170 to 180; 175 to 185; 180 to 190; 185 to
195; 190 to 200; 195 to 205; 200 to 210; 205 to 215; 210 to 220;
215 to 225; 220 to 230; 225 to 235; 230 to 240; 235 to 245; or 240
to 250 .mu.g/mL. In a study conducted by administering the
self-emulsifying composition at such a timing as before,
immediately after or after meals at an EPA dose of 3600 mg, the
maximum .omega.3 PUFA plasma concentration may be specified to be:
10 to 50; 50 to 100; 100 to 150; 150 to 200; 200 to 250; 250 to
300; 300 to 350; 350 to 400; 400 to 450; 450 to 500; 500 to 600;
600 to 700; 700 to 800; 800 to 900; 900 to 1000; 10 to 30; 20 to
40; 30 to 50; 40 to 60; 50 to 70; 60 to 80; 70 to 90; 80 to 100; 90
to 110; 100 to 120; 110 to 130; 120 to 140; 130 to 150; 140 to 160;
150 to 170; 160 to 180; 170 to 190; 180 to 200; 190 to 210; 200 to
220; 220 to 240; 240 to 260; 260 to 280; 280 to 300; 10 to 20; 15
to 25; 20 to 30; 25 to 35; 30 to 40; 35 to 45; 40 to 50; 45 to 55;
50 to 55; 53 to 58; 55 to 60; 58 to 63; 60 to 65; 63 to 68; 65 to
70; 68 to 73; 70 to 75; 73 to 78; 75 to 80; 78 to 83; 80 to 85; 83
to 88; 85 to 90; 88 to 93; 90 to 95; 93 to 98; 95 to 100; 98 to
103; 100 to 105; 103 to 108; 105 to 110; 108 to 113; 110 to 115;
113 to 118; 115 to 120; 118 to 123; 120 to 125; 123 to 128; 125 to
130; 128 to 133; 130 to 135; 133 to 138; 135 to 140; 138 to 143;
140 to 145; 143 to 148; 145 to 150; 150 to 160; 155 to 165; 160 to
170; 165 to 175; 170 to 180; 175 to 185; 180 to 190; 185 to 195;
190 to 200; 195 to 205; 200 to 210; 205 to 215; 210 to 220; 215 to
225; 220 to 230; 225 to 235; 230 to 240; 235 to 245; or 240 to 250
.mu.g/mL.
[0238] The area under the blood .omega.3 PUFA concentration vs time
curve from zero to 72 hours after the administration in a study
conducted by administering the self-emulsifying composition at such
a timing as before, immediately after or after meals at an EPA dose
of 1800 mg may be specified to be: 500 to 1500; 1000 to 2000; 1500
to 2500; 2000 to 3000; 2500 to 3500; 3000 to 4000; 500 to 1000; 750
to 1250; 1000 to 1500; 1250 to 1750; 1500 to 2000; 1750 to 2250;
2000 to 2500; 2250 to 2750; 2500 to 3000; 2750 to 3250; 3000 to
3500; 3250 to 3750; 3500 to 4000; 3750 to 4250; 4000 to 4500; 4250
to 4750; 4500 to 5000; 500 to 700; 600 to 800; 700 to 900; 800 to
1000; 900 to 1100; 1000 to 1200; 1100 to 1300; 1200 to 1400; 1300
to 1500; 1400 to 1600; 1500 to 1700; 1600 to 1800; 1700 to 1900;
1800 to 2000; 1900 to 2100; 2000 to 2200; 2100 to 2300; 2200 to
2400; 2300 to 2500; 2400 to 2600; 2500 to 2700; 2600 to 2800; 2700
to 2900; 2800 to 3000; 2900 to 3100; 3000 to 3200; 3100 to 3300;
3200 to 3400; 3300 to 3500; 3400 to 3600; 3500 to 3700; 3600 to
3800; 3700 to 3900; 3800 to 4000; 3900 to 4100; 4000 to 4200; 4100
to 4300; 4200 to 4400; 4300 to 4500; 500 to 600; 550 to 650; 600 to
700; 650 to 750; 700 to 800; 750 to 850; 800 to 900; 850 to 950;
900 to 1000; 950 to 1050; 1000 to 1100; 1050 to 1150; 1100 to 1200;
1150 to 1250; 1200 to 1300; 1250 to 1350; 1300 to 1400; 1350 to
1450; 1400 to 1500; 1450 to 1550; 1500 to 1600; 1550 to 1650; 1600
to 1700; 1650 to 1750; 1700 to 1800; 1750 to 1850; 1800 to 1900;
1850 to 1950; 1900 to 2000; 1950 to 2050; 2000 to 2100; 2050 to
2150; 2100 to 2200; 2150 to 2250; 2200 to 2300; 2250 to 2350; 2300
to 2400; 2350 to 2450; 2400 to 2500; 2450 to 2550; 2500 to 2600;
2550 to 2650; 2600 to 2700; 2650 to 2750; 2700 to 2800; 2750 to
2850; 2800 to 2900; 2850 to 2950; 2900 to 3000; 2950 to 3050; 3000
to 3100; 3150 to 3250; 3200 to 3300; 3250 to 3350; 3300 to 3400;
3350 to 3450; 3400 to 3500; 3500 to 3600; 3600 to 3700; 3700 to
3800; 3800 to 3900; 3900 to 4000; 4000 to 4100; 4100 to 4200; 4200
to 4300; 4300 to 4400; or 4400 to 4500 .mu.g/mL hr. In a study
conducted by administering the self-emulsifying composition at such
a timing as before, immediately after or after meals at an EPA dose
of 3600 mg, the area under the blood .omega.3 PUFA concentration vs
time curve as above may be specified to be: 500 to 1500; 1000 to
2000; 1500 to 2500; 2000 to 3000; 2500 to 3500; 3000 to 4000; 500
to 1000; 750 to 1250; 1000 to 1500; 1250 to 1750; 1500 to 2000;
1750 to 2250; 2000 to 2500; 2250 to 2750; 2500 to 3000; 2750 to
3250; 3000 to 3500; 3250 to 3750; 3500 to 4000; 3750 to 4250; 4000
to 4500; 4250 to 4750; 4500 to 5000; 500 to 700; 600 to 800; 700 to
900; 800 to 1000; 900 to 1100; 1000 to 1200; 1100 to 1300; 1200 to
1400; 1300 to 1500; 1400 to 1600; 1500 to 1700; 1600 to 1800; 1700
to 1900; 1800 to 2000; 1900 to 2100; 2000 to 2200; 2100 to 2300;
2200 to 2400; 2300 to 2500; 2400 to 2600; 2500 to 2700; 2600 to
2800; 2700 to 2900; 2800 to 3000; 2900 to 3100; 3000 to 3200; 3100
to 3300; 3200 to 3400; 3300 to 3500; 3400 to 3600; 3500 to 3700;
3600 to 3800; 3700 to 3900; 3800 to 4000; 3900 to 4100; 4000 to
4200; 4100 to 4300; 4200 to 4400; 4300 to 4500; 500 to 600; 550 to
650; 600 to 700; 650 to 750; 700 to 800; 750 to 850; 800 to 900;
850 to 950; 900 to 1000; 950 to 1050; 1000 to 1100; 1050 to 1150;
1100 to 1200; 1150 to 1250; 1200 to 1300; 1250 to 1350; 1300 to
1400; 1350 to 1450; 1400 to 1500; 1450 to 1550; 1500 to 1600; 1550
to 1650; 1600 to 1700; 1650 to 1750; 1700 to 1800; 1750 to 1850;
1800 to 1900; 1850 to 1950; 1900 to 2000; 1950 to 2050; 2000 to
2100; 2050 to 2150; 2100 to 2200; 2150 to 2250; 2200 to 2300; 2250
to 2350; 2300 to 2400; 2350 to 2450; 2400 to 2500; 2450 to 2550;
2500 to 2600; 2550 to 2650; 2600 to 2700; 2650 to 2750; 2700 to
2800; 2750 to 2850; 2800 to 2900; 2850 to 2950; 2900 to 3000; 2950
to 3050; 3000 to 3100; 3150 to 3250; 3200 to 3300; 3250 to 3350;
3300 to 3400; 3350 to 3450; 3400 to 3500; 3500 to 3600; 3600 to
3700; 3700 to 3800; 3800 to 3900; 3900 to 4000; 4000 to 4100; 4100
to 4200; 4200 to 4300; 4300 to 4400; or 4400 to 4500
.mu.g/mLhr.
[0239] The time until the maximum plasma concentration is attained
in a study conducted by administering the self-emulsifying
composition at such a timing as before, immediately after or after
meals at an EPA dose of 1800 mg or 3600 mg may be specified to be:
0 to 2; 1 to 3; 2 to 4; 3 to 5; 4 to 6; 5 to 7; 6 to 8; 7 to 9; 8
to 10; 0 to 1; 0.5 to 1.5; 1 to 2; 1.5 to 2.5; 2 to 3; 2.5 to 3.5;
3 to 4; 3.5 to 4.5; 4 to 5; 4.5 to 5.5; 5 to 6; 5.5 to 6.5; 6 to 7;
6.5 to 7.5; 7 to 8; 7.5 to 8.5; 8 to 9; 8.5 to 9.5; 9 to 10; 0 to
0.5; 0.3 to 0.8; 0.5 to 1; 0.8 to 1.3; 1 to 1.5; 1.3 to 1.8; 1.5 to
2; 1.8 to 2.3; 2 to 2.5; 2.3 to 2.8; 2.5 to 3; 2.8 to 3.3; 3 to
3.5; 3.3 to 3.8; 3.5 to 4; 3.8 to 4.3; 4 to 4.5; 4.3 to 4.8; 4.5 to
5; 4.8 to 5.3; 5 to 5.5; 5.3 to 5.8; 5.5 to 6; 5.8 to 6.3; 6 to
6.5; 6.3 to 6.8; 6.5 to 7; 6.8 to 7.3; 7 to 7.5; 7.3 to 7.8; 7.5 to
8; 7.8 to 8.3; 8 to 8.5; 8.3 to 8.8; 8.5 to 9; 8.8 to 9.3; 9 to
9.5; 9.3 to 9.8; or 9.5 to 10 hours.
[0240] The plasma elimination half-life in a study conducted by
administering the self-emulsifying composition at such a timing as
before, immediately after or after meals at an EPA dose of 1800 mg
or 3600 mg may be specified to be: 0 to 50; 25 to 75; 50 to 100; 75
to 125; 100 to 150; 125 to 175; 150 to 200; 0 to 20; 10 to 30; 20
to 40; 30 to 50; 40 to 60; 50 to 70; 60 to 80; 70 to 90; 80 to 100;
90 to 110; 100 to 120; 110 to 130; 120 to 140; 130 to 150; 0 to 10;
5 to 15; 10 to 20; 15 to 25; 20 to 30; 25 to 35; 30 to 40; 35 to
45; 40 to 50; 45 to 55; 50 to 60; 55 to 65; 60 to 70; 65 to 75; 70
to 80; 75 to 85; 80 to 90; 85 to 95; 90 to 100; 95 to 105; 100 to
110; 105 to 115; or 110 to 120 hours.
[0241] The present invention may be defined by a combination of two
or more selected from among the maximum .omega.3 PUFA plasma
concentration, the area under the blood .omega.3 PUFA concentration
vs time curve from zero to 72 hours after the administration, the
time until the maximum plasma concentration is attained, and the
plasma elimination half-life.
[0242] The self-emulsifying composition of the present invention
may also contain additives such as an emulsification aid,
stabilizer, antiseptic, surfactant, and antioxidant. Exemplary
emulsification aids include fatty acids containing 12 to 22 carbon
atoms such as stearic acid, oleic acid, linoleic acid, palmitic
acid, linolenic acid, and myristic acid and their salts. Exemplary
stabilizers include phosphatidic acid, ascorbic acid, glycerin, and
cetanols, and exemplary antiseptics include ethyl paraoxybenzoate
and propyl paraoxybenzoate. Exemplary antioxidants include
oil-soluble antioxidants such as butylated hydroxy toluene,
butylated hydroxy anisole, propyl gallate, propyl gallate,
pharmaceutically acceptable quinone, astaxanthin, and
.alpha.-tocopherol.
[0243] In addition, an adequate carrier or vehicle, a colorant, a
flavor, and optionally, a vegetable oil and an additive such as
non-toxic organic solvent or non-toxic solubilizing agent,
emulsifier, suspending agent (for example, Tween 80 and gum arabic
solution), isotonic agent, pH adjusting agent, stabilizer,
corrective, flavoring agent, preservative, antioxidant, or
absorption promoter commonly used in the art may be adequately
combined with the inventive composition to prepare an appropriate
pharmaceutical preparation.
[0244] More specifically, since the .omega.3 PUFA is highly
unsaturated, effective amount of an oil-soluble antioxidant, for
example, at least one member selected from butylated
hydroxytoluene, butylated hydroxyanisole, propyl gallate, propyl
gallate, pharmaceutically acceptable quinone, astaxanthin, and
.alpha.-tocopherol is preferably incorporated in the
composition.
[0245] Since the self-emulsifying composition of the present
invention is also used for pharmaceutical application, it
preferably has good appearance, self-emulsifying property,
composition dispersibility, emulsion stability, and storage
stability. The appearance of the self-emulsifying composition is
such that the composition is not separated, clouded, solidified, or
precipitated, but transparent. The composition having poor
appearance may be pharmaceutically unsuitable, and such composition
may be insufficient in required performance such as
self-emulsifying property.
[0246] With regard to the storage temperature, the self-emulsifying
composition and the preparation prepared by encapsulating such
composition is preferably transparent at both low temperature and
high temperature in view of its use in cold district or hot
environment.
[0247] In the case of the self-emulsifying composition having good
self-emulsifying property, good dispersibility of the composition,
and high emulsion stability, the composition rapidly disperses upon
contact with water to form a microemulsion having adequate emulsion
droplet diameter. Absorbability of an oil such as EPA-E is related
to the size of the emulsion droplet diameter, and degree of the
absorbability upon administration to the animal can be estimated by
measuring the emulsion droplet diameter.
[0248] In the present invention, the "mean droplet diameter" is the
value of volume mean diameter among droplets of the emulsified
composition measured by using a particle size analyzer (for
example, Nanotorac manufactured by Nikkiso Co., Ltd.) with water
being used for the dispersion medium according to standard
measurement method (for example, set zero time of 30 seconds,
measurement time of 30 seconds, average of three measurements). The
mean droplet diameter when the self-emulsifying composition of the
present invention is dispersed in water or the like is not
particularly limited as long as it is up to 2 .mu.m, and the
product has good emulsion dispersibility, good emulsion stability,
or good absorbability, and the mean droplet diameter is typically
up to 1.5 .mu.m, more preferably up to 1.0 .mu.m, still more
preferably up to 0.5 .mu.m, and most preferably up to 0.3
.mu.m.
[0249] The self-emulsifying composition of the present invention
may be used by combining with a second effective component. The
second effective component may be any component adequately selected
depending on the intended type and severity of the disease as long
as it does not adversely affect the merits of the .omega.3 PUFAs.
Exemplary such second effective components include therapeutic
agents for hyperlipidemia, antihypertensives, antidiabetics,
antioxidants, blood flow improving agents, bile acid derivatives,
therapeutic agents for NAFLD and NASH, as well as progression
suppressants and therapeutic agents for cognitive impairment.
[0250] Examples of a favorable second effective component include
such therapeutic agents for hyperlipidemia as polyene phosphatidyl
choline, unsaponifiable matter in soybean oil (soysterol), gamma
orizanol, riboflavin butyrate, dextran sulfate sodium sulfur 18,
pantethine, and elastase. Also included are statins such as
pravastatin, simbastatin, atorvastatin, fluvastatin, pitavastatin,
rosuvastatin and cerivastatin; fibrates such as simfibrate,
clofibrate, clinofibrate, bezafibrate and fenofibrate; lipolytic
enzyme inhibitors such as orlistat and cetilistat; resins such as
cholestyramine and cholestyramide; and ezetimibe.
[0251] Exemplary antihypertensives include: angiotensin II receptor
antagonists such as irbesartan, olmesartan medoxomil, candesartan
cilexetil, telmisartan, valsartan, and losartan potassium;
angiotensin converting enzyme inhibitors such as alacepril,
imidapril hydrochloride, enalapril maleate, captopril, quinapril
hydrochloride, cilazapril hydrate, temocapril hydrochloride,
delapril hydrochloride, trandolapril, benazepril hydrochloride,
perindopril, and lisinopril hydrate; calcium antagonists such as
azelnidipine, amlodipine besylate, aranidipine, efonidipine
hydrochloride, cilnidipine, nicardipine hydrochloride, nifedipine,
nimodipine, nitrendipine, nilvadipine, barnidipine hydrochloride,
felodipine, benidipine, and manidipin; .alpha.-receptor blockers
such as tolazoline and phentolamine; .beta.-receptor blockers such
as atenolol, metoprolol, acebutolol, propranolol, pindolol,
carvedilol, and labetalol hydrochloride; .alpha.-receptor
stimulants such as clonidine and methyldopa; and diuretics such as
eplerenone, hydrochlorothiazide and furosemide.
[0252] Exemplary antidiabetics include: .alpha.-glucosidase
inhibitors such as acarbose, voglibose and miglitol; sulfonylurea
hypoglycemic agents such as gliclazide, glibenclamide, glimepiride
and tolbutamide; short-acting insulin secretagogues such as
nateglinide and mitiglinide; biguanide hypoglycemic agents such as
metformin hydrochloride and buformin hydrochloride; dipeptidyl
phosphatase-4 inhibitors such as sitagliptin, vildagliptin,
alogliptin, linagliptin, teneligliptin, anagliptin and saxagliptin;
thiazolidines such as pioglitazone hydrochloride and rosiglitazone
maleate; glucagon-like peptide 1 derivatives such as exenatide and
liraglutide; and sodium-glucose cotransporter 2 inhibitors such as
ipragliflozin, dapagliflozin, luseogliflozin, tofogliflozin,
canagliflozin and empagliflozin.
[0253] Exemplary antioxidants include such vitamins as ascorbic
acid (vitamin C), tocopherol (vitamin E) and tocopherol nicotinate
ester, N-acetylcysteine, and probucol.
[0254] Exemplary blood flow improving agents include cilostazol,
ticlopidine hydrochloride, alprostadil, limaprost, beraprost
sodium, sarpogrelate hydrochloride, argatroban, naftidrofuryl,
isoxsuprine hydrochloride, batroxobin, dihydroergotoxine mesylate,
tolazoline hydrochloride, hepronicate, and shimotsuto extract.
[0255] Exemplary bile acid derivatives include ursodeoxycholic
acid, chenodeoxycholic acid, bile powder, deoxycholic acid, cholic
acid, bile extract, bear bile, oriental bezoar, and dehydrocholic
acid. Favorable examples are biotin (vitamin B7), cyanocobalamin
(vitamin B12), pantothenic acid (vitamin B5), folic acid (vitamin
B9), thiamine (vitamin B1), vitamin A, vitamin D, vitamin K,
tyrosine, pyridoxine (vitamin B6), branched amino acids such as
leucine, isoleucine and valine, calcium, iron, zinc, copper,
magnesium, and the like. Also favorable are such ingredients of
foods for specified health use and foods with nutrient function
claims as soybean proteins, chitosan, low molecular-weight sodium
alginate, dietary fiber derived from psyllium seed husks, soybean
peptides bound to phospholipids, plant sterol esters, plant stanol
esters, diacylglycerol, globin proteolysis products, and tea
catechin.
[0256] Exemplary therapeutic agents for NAFLD and NASH include the
statins such as pravastatin, simbastatin, atorvastatin,
fluvastatin, pitavastatin, rosuvastatin and cerivastatin; the
angiotensin II receptor antagonists such as irbesartan, olmesartan
medoxomil, candesartan lexetil, telmisartan, valsartan, and
losartan potassium; the biguanide hypoglycemic agents such as
metformin hydrochloride and buformin hydrochloride; and the
thiazolidines such as pioglizone hydrochloride and rosiglitazone
maleate as mentioned above, as well as aspirin and farnesoid X
receptor (hereafter abbreviated as FXR) ligands such as
ursodeoxycholic acid, chenodeoxycholic acid and obeticholic
acid.
[0257] Exemplary progression suppressants and therapeutic agents
for cognitive impairment include acetylcholineesterase inhibitors
such as donepezil hydrochloride and galantamine hydrobromide; NMDA
receptor inhibitors such as memantine hydrochloride; antiplatelets
such as aspirin, clopidogrel sulfate, cilostazol, and ticlopidine
hydrochloride; and factor Xa inhibitors such as rivaroxaban and
apixaban. In addition, the therapeutic agents for hyperlipidemia,
antihypertensives, antidiabetics, antioxidants and blood flow
improving agents as mentioned above are also usable as progression
suppressants and therapeutic agents for cognitive impairment.
[0258] To realize pharmacological actions of the .omega.3 PUFA, the
self-emulsifying composition of the present invention preferably
has at least one merit selected from good appearance, good
self-emulsifying property, high composition dispersibility, high
emulsion stability, high storage stability (including the stability
at low and high temperatures), high absorbability, in particular
high absorbability and high absorption speed under fasting
conditions, and convenience in taking the preparation or
compliance.
[0259] The self-emulsifying composition of the present invention is
well adapted for use as a therapeutic agent for treating various
diseases of animals, mammals in particular, that is to say, is
usable as, for instance, therapeutic agent for dyslipidemia
(hypercholesterolemia, LDL hypercholesterolemia, non-HDL
hypercholesterolemia, VLDL hypercholesterolemia, HDL
hypocholesterolemia, hypertriglyceridemia, apo B
hyperlipoproteinemia, apo A-I hypolipoproteinemia, and so forth),
therapeutic agent for postprandial hypertriglyceridemia,
anti-arteriosclerotic, platelet aggregation suppressant,
therapeutic agent for peripheral circulatory insufficiency,
prophylactic agent for cardiovascular events, therapeutic agent for
inflammatory disease (NAFLD, NASH, and so forth), progression
suppressant and therapeutic agent for cognitive impairment
(dementia of the Alzheimer's type, cerebrovascular dementia, mixed
type of dementia, and so forth), anticancer agent, and therapeutic
agent for central disease (depression, depressive condition,
obsessive-compulsive disorder, social anxiety disorder, panic
disorder, and so forth). In the treatment of the diseases as above,
the inventive self-emulsifying composition is not particularly
limited in frequency of administration per day, and is preferably
administered one time a day at the entire daily dose or two or
three times a day at divided doses, with one or two time
administration per day being more preferable and one time
administration per day most preferable.
[0260] The self-emulsifying composition of the present invention is
particularly effective for the amelioration or treatment of
dyslipidemia and postprandial hypertriglyceridemia, and the
prevention of their recurrence or progression to metabolic
syndrome, cardiocerebrovascular events, and ulcer or gangrene at a
limb distal end. Exemplary mammals include human, domestic animals
such as cattle, horse, and pig, and companion animals such as dog,
cat, rabbit, rat, and mouse, and the preferred is human. More
specifically, the self-emulsifying composition of the present
invention is anticipated to show ameliorating or therapeutic
effects for dyslipidemia and postprandial hypertriglyceridemia in
patients with dyslipidemia suffering from increase in the blood
lipid, exhibiting insulin resistance or suffering from increase in
the blood pressure, such as metabolic syndrome patients.
EXAMPLES
[0261] Next, the present invention is described in further detail
by referring to the following Examples and Comparative Examples
which by no means limit the scope of the invention.
Example 1
[0262] In a vessel, 0.05 g of water, 0.95 g of polyoxyethylene (20)
sorbitan oleate and 4 g of EPA-E as weighed were placed and sealed,
and mixed under heating to about 70.degree. C. to thereby prepare a
self-emulsifying composition. The self-emulsifying composition thus
prepared was sealed after purging with nitrogen, and stored at room
temperature until the evaluation was conducted. Formulation of the
self-emulsifying composition is shown in Table 1. In the table, the
symbol "-" means that the component in question was not added or
not measured.
Examples 2 through 8 and Comparative Examples 1 through 3
[0263] The self-emulsifying compositions of Examples 2 through 9
and the compositions of Comparative Examples 1 through 3 were
prepared and stored by repeating the method of Example 1 so that
the compositional ratios were as shown in Table 1. Formulations of
the self-emulsifying compositions are shown in Table 1.
Examples 9 through 17 and Comparative Examples 4 through 8
[0264] The self-emulsifying compositions of Examples 10 through 15
and the compositions of Comparative Examples 4 through 8 were
prepared and stored by repeating the method of Example 1 so that
the compositional ratios were as shown in Table 2. Formulations of
the self-emulsifying compositions are shown in Table 2.
Test Example 1 <Evaluation of Appearance>
[0265] The self-emulsifying compositions and the compositions of
Comparative Examples as produced by the above production method
were allowed to stand at room temperature, and after about 1 hour,
their appearance was evaluated. When the composition was
homogeneous due to its good compatibility, the composition was
evaluated as "transparent." The composition was evaluated as
"separated" when the separation was observed, and "cloudy" when
opacity was observed.
[0266] The results are shown in Tables 1 and 2.
Test Example 2 <Evaluation of Self-Emulsifying Property>
[0267] The self-emulsifying compositions and the compositions of
Comparative Examples as produced by the above production method
were evaluated for self-emulsifying property by adding 10 .mu.L of
each composition dropwise to 5 mL of purified water or first fluid
for dissolution test of Japanese Pharmacopeia at 37.degree. C. in
the test tube. The composition which spontaneously emulsified just
by the dropwise addition was evaluated as "good," and the case
which did not become an emulsion just by the dropwise addition was
evaluated as "poor." The composition was then lightly stirred under
consistent condition, and other properties were examined. With
regard to the dispersibility of the composition, the composition
was evaluated as "good" when dispersed and as "poor" when partly
left undispersed as a mass. With regard to the emulsion stability,
the composition was evaluated as "good" when no oil separation was
observed, and as "poor" when oil separation was observed. It is to
be noted that the compositions which were not evaluated as
"transparent" in the appearance evaluation were not evaluated in
such properties since inhomogeneous compositions were conceived to
be inadequate for property evaluation.
[0268] The results are shown in Tables 1 and 2.
Test Example 3 <Evaluation of Emulsion Droplet Diameter>
Conditions for the measurement of mean droplet diameter and
measurement results.
[0269] Using about 1.5 mL of the emulsified composition as obtained
in Test Example 2, the mean droplet diameter (volume mean diameter)
was measured by a particle size analyzer (Nanotrac, manufactured by
Nikkiso Co., Ltd.) using water as a dispersion medium.
[0270] The results are shown in Tables 1 and 2.
Test Example 4 <Evaluation of the Appearance after Storage under
Severe Conditions>
[0271] The compositions which were evaluated as "transparent" in
Test Example 1 were allowed to stand and stored overnight (for
about 12 hours) at 5.degree. C. or 40.degree. C. before their
appearance was evaluated. When the composition was homogeneous due
to its good compatibility, the composition was evaluated as
"transparent." The composition was evaluated as "separated" when
the separation was observed, and as "cloudy" when opacity was
observed.
[0272] The results are shown in Tables 1 and 2. In the tables, the
symbol "-" means that the component in question was not added or
not measured.
TABLE-US-00001 TABLE 1 (1/2) Comp. Comp. Comp. Component Ex. 1 Ex.
2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Ex. 8 Ex. 1 Ex. 2 Ex. 3 Ethyl 80.0
84.0 80.0 75.0 84.0 80.0 80.0 76.0 80.0 80.0 94.0 eicosapentaenoate
Purified water 1.0 1.0 1.0 2.0 1.0 1.0 0.5 4.0 0.0 8.0 1.0
Polyoxyethylene (20) 19.0 8.6 10.0 -- 7.0 17.0 10.5 10.0 10.0 7.0
5.0 sorbitan oleate Polyoxyethylene (20) -- -- -- 15.0 -- -- -- --
-- -- -- sorbitan trioleate Sorbitan -- -- -- -- 3.0 -- 4.0 5.0 5.0
2.0 -- monolaurate Sorbitan -- 6.4 -- -- -- -- 1.0 -- -- -- --
sesquioleate Decaglyceryl -- -- 9.0 -- -- -- -- -- -- -- -- oleate
Polyoxyl 35 -- -- -- 8.0 4.0 -- 4.0 5.0 5.0 3.0 -- castor oil
Propylene glycol -- -- -- -- 1.0 -- -- -- -- -- -- fatty acid ester
Soybean -- -- -- -- -- 2.0 -- -- -- -- -- lecithin Total 100.00
100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00
100.00 (2/2) Comp. Comp. Comp. Ex. 1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6
Ex. 7 Ex. 8 Ex. 1 Ex. 2 Ex. 3 Test Ex. 1 Appear- Trans- Trans-
Trans- Trans- Trans- Trans- Trans- Trans- Separ- Separ- Separ- ance
parent parent parent parent parent parent parent parent ated ated
ated Test Ex. 2 Self- Good Good Good Good Good Good Good Good Not
Not Not emulsifying evaluated evaluated evaluated property
Composition Good Good Good Good Good Good Good Good dispersibility
Emulsion Good Good Good Good Good Good Good Good stability Test Ex.
3 37.degree. C. 0.23 0.41 0.19 0.19 0.22 0.25 0.21 0.20 Emulsion
Purified droplet water (.mu.m) diameter 37.degree. C. 0.29 0.29
0.87 0.24 0.18 0.27 0.18 0.23 Japanese Pharmacopeia 1st liquid
(.mu.m) Test Ex. 4 Stored at Trans- Trans- Trans- Trans- Trans-
Trans- Trans- Trans- Appearance 5.degree. C. parent parent parent
parent parent parent parent parent Stored at Trans- Trans- Trans-
Trans- Trans- Trans- Trans- Trans- 40.degree. C. parent parent
parent parent parent parent parent parent
TABLE-US-00002 TABLE 2 (1/4) Component Ex. 9 Ex. 10 Ex. 11 Ex. 12
Ex. 13 Ex. 14 Ex. 15 Ex. 16 Ex. 17 Ethyl 75.0 80.0 80.0 82.0 84.0
80.0 84.0 80.0 80.0 eicosapentaenoate Purified water 2.0 2.0 1.0
1.0 1.0 1.0 1.0 1.0 1.0 Polyoxyethylene (20) -- -- -- -- 10.0 10.0
8.0 10.0 10.0 sorbitan oleate Sorbitan -- 7.5 5.0 5.0 4.0 4.0 4.0
4.0 -- monolaurate Sorbitan -- -- -- -- -- -- -- -- -- sesquioleate
Sorbitan -- -- -- -- -- -- -- -- 4.0 monooleate Glyceryl -- -- --
-- -- -- -- 1.0 -- monooleate Decaglyceryl 15.0 -- 9.0 7.0 8.0 --
-- -- -- oleate Polyoxyl 35 8.0 10.5 5.0 5.0 3.0 5.0 3.0 5.0 5.0
castor oil Soybean -- -- -- -- -- -- -- -- -- lecithin Propylene --
-- -- -- -- -- -- -- -- Glycol Ethanol -- -- -- -- -- -- -- -- --
Total 100.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00
100.00 (2/4) Ex. 9 Ex. 10 Ex. 11 Ex. 12 Ex. 13 Ex. 14 Ex. 15 Ex. 16
Ex. 17 Test Ex. 1 Appear- Trans- Trans- Trans- Trans- Trans- Trans-
Trans- Trans- Trans- ance parent parent parent parent parent parent
parent parent parent Test Ex. 2 Self- Good Good Good Good Good Good
Good Good Good emulsifying property Composition Good Good Good Good
Good Good Good Good Good dispersibility Emulsion Good Good Good
Good Good Good Good Good Good stability Test Ex. 3 37.degree. C.
0.18 0.25 0.22 0.29 0.29 0.18 0.18 0.21 0.21 Emulsion Purified
droplet water (.mu.m) diameter 37.degree. C. 0.18 0.34 0.22 0.25
0.26 0.29 0.17 0.22 0.27 Japanese Pharmacopeia 1st liquid (.mu.m)
Test Ex. 4 Stored at Trans- Trans- Trans- Trans- Trans- Trans-
Trans- Trans- Trans- Appearance 5.degree. C. parent parent parent
parent parent parent parent parent parent Stored at Trans- Trans-
Trans- Trans- Trans- Trans- Trans- Trans- Trans- 40.degree. C.
parent parent parent parent parent parent parent parent parent
(3/4) Comp. Comp. Comp. Comp. Comp. Component Ex. 4 Ex. 5 Ex. 6 Ex.
7 Ex. 8 Ethyl 80.0 75.2 70.0 80.0 80.0 eicosapentaenoate Purified
water -- -- -- -- 1.0 Polyoxyethylene (20) -- 5.8 -- 11.4 --
sorbitan oleate Sorbitan 7.5 -- 14.3 -- -- monolaurate Sorbitan --
-- -- 8.6 -- sesquioleate Sorbitan -- -- -- -- -- monooleate
Glyceryl -- -- -- -- -- monooleate Decaglyceryl -- -- -- -- --
oleate Polyoxyl 35 10.5 5.8 15.7 -- 19.0 castor oil Soybean -- 6.5
-- -- -- lecithin Propylene -- 6.7 -- -- -- Glycol Ethanol 2.0 --
-- -- -- Total 100.00 100.00 100.00 100.00 100.00 (4/4) Comp. Comp.
Comp. Comp. Comp. Ex. 4 Ex. 5 Ex. 6 Ex. 7 Ex. 8 Test Ex. 1 Appear-
Separ- Trans- Trans- Trans- Separ- ance ated parent parent parent
ated Test Ex. 2 Self- Not Good Good Good Not emulsifying evaluated
evaluated property Composition Good Good Good dispersibility
Emulsion Good Good Good stability Test Ex. 3 37.degree. C. 0.18
0.17 0.68 Emulsion Purified droplet water (.mu.m) diameter
37.degree. C. 0.18 0.48 0.33 Japanese Pharmacopeia 1st liquid
(.mu.m) Test Ex. 4 Stored at Trans- Precip- Separ- Appearance
5.degree. C. parent itated ated Stored at Separ- Trans- Separ-
40.degree. C. ated parent ated
[0273] The composition of Example 1 contained a polyoxyethylene
sorbitan fatty acid ester as the only emulsifier together with a
specified amount of water, and, as shown in Table 1, had good
appearance and excellent properties including self-emulsifying
property. This result indicates that the merits of the present
invention are realized even by a composition only containing a
polyoxyethylene sorbitan fatty acid ester as an emulsifier.
[0274] The compositions of Examples 2 through 8 and 14 through 17
had various emulsifiers added thereto apart from the
polyoxyethylene sorbitan fatty acid ester as an emulsifier, and
further contained water. The compositions were excellent in
appearance, self-emulsifying property and other properties, as was
the case with the composition of Example 1.
[0275] The compositions of Examples 7 and 8 as well as Comparative
Examples 1 and 2 contained water in varied amounts. The composition
of Comparative Example 1 contained no water, and became separated.
The composition of Comparative Example 2, which contained 8% by
weight of water, also became separated.
[0276] In the present invention, water is used instead of ethanol
or a polyhydric alcohol in order to improve the compatibility of a
composition. The composition having contained no water was
separated due to its inadequate compatibility. At the same time,
the composition with too high a water content was also separated.
Separation did not occur in the compositions of Examples 1 through
9 each having contained 0.5 to 4% by weight of water. These results
indicate that addition of water in a specified amount of about 0.5%
to about 6% by weight is important in preparing the inventive
composition which is excellent in appearance and properties.
[0277] The composition of Comparative Example 3, which contained
water and had a high ethyl eicosapentaenoate content of 94% by
weight, became separated. It is considered that even a composition
containing the specified amount of water will be separated if it
has an oil content higher than 70 to 90% by weight because the
amount of emulsifiers containable is reduced relative to the amount
of oil components.
[0278] The composition of Comparative Example 4 contained no water
but ethanol, and separation was observed in its appearance
evaluation.
[0279] The composition of Example 10 was prepared by replacing the
ethanol as used in Comparative Example 4 by water, and was good in
appearance. It is considered that, in the case of water, a content
of about 2% by weight can bring about an adequate compatibility,
while separation occurred in the composition of Comparative Example
4 having contained 2% by weight of ethanol due to the shortage of
ethanol.
[0280] The composition of Comparative Example 5 contained no water
but lecithin and a polyhydric alcohol. As in the case of Example 1
and the like, this composition had good appearance and excellent
properties including self-emulsifying property at room
temperature.
[0281] The composition, however, was separated after overnight
storage at 40.degree. C., which demonstrates that addition of the
specified amount of water allows a composition of good appearance
even in the environment at higher or lower temperatures.
[0282] The compositions of Examples 9 through 13 each contained at
least two emulsifiers selected from among a sorbitan fatty acid
ester, a glycerin fatty acid ester and a polyoxyl castor oil, and
further contained water. As shown in Table 2, the compositions had
good appearance and were excellent in self-emulsifying property and
other properties.
[0283] On the other hand, the composition of Comparative Example 8,
which contained only one selected from among the above emulsifiers,
had a separated appearance. The results indicate that two or more
emulsifiers need to be selected.
[0284] The compositions of Comparative Examples 5 through 7 each
contained emulsifiers selected from among a polyoxyethylene
sorbitan fatty acid ester, a sorbitan fatty acid ester and a
polyoxyl castor oil, and contained no water. Although the
compositions were transparent in appearance at room temperature,
separation or precipitation occurred in the compositions during the
storage at lower and/or higher temperatures because of their not
containing water.
[0285] The composition of Comparative Example 8 only contained a
polyoxyl castor oil as an emulsifier, and became separated at
temperatures of 5.degree. C. and 40.degree. C. In the present
invention, in order to obtain the self-emulsifying composition
which has good performance if containing the specified amount of
water, it is necessary to use, as an emulsifying agent, i) a
polyoxyethylene sorbitan fatty acid ester or ii) at least two
emulsifiers selected from among a sorbitan fatty acid ester, a
glycerin fatty acid ester and a polyoxyethylene castor oil. It is
seen from this Comparative Example that the use of a
polyoxyethylene castor oil alone does not allow the
self-emulsifying composition as expected. In other words, it has
been found that a certain emulsifier or emulsifying agent needs to
be used for the self-emulsifying composition which has good
performance if containing the specified amount of water.
Test Example 5 <Pharmacokinetics in Beagles>
[0286] The composition of Example 14 was orally administered to 6
male beagles (at the age of 2 to 6 years with the body weight of 13
kg, 3 Marshall beagles and 3 Nosan beagles) under fasting
conditions, and blood EPA concentration was evaluated. The test
animals had been fasted since 18 hours or more before the
administration, and each animal was administered with the
composition in an amount corresponding to 600 mg of the EPA-E.
Blood was collected before the administration, and 0.5, 1, 1.5, 2,
3, 4, 6, 8, and 24 hours after the administration, and plasma was
separated to measure plasma EPA concentration by LC/MS/MS (method
in which a sample is isolated by liquid chromatography, then
subjected to mass spectrometry to conduct separation and
measurement thereon). The control group was administered with the
EPA-E stock solution encapsulated in a capsule.
[0287] Table 3 shows the maximum blood concentration (Cmax), the
area under the blood concentration vs time curve from zero to two
hours (AUC.sub.0-2) and the area under the blood concentration vs
time curve from zero to 24 hours (AUC.sub.0-24) as calculated from
the test results. In the calculation of each parameter, correction
was made by subtracting the blood EPA concentration before the
administration from the measured blood concentration.
TABLE-US-00003 TABLE 3 Ex. 14 EPA-E Stock solution Results of Test
Ex. 5 (Fasted) (Control fasted) Cmax (.mu.g/mL) 120.7 16.6
AUC.sub.0-2 (.mu.g/mL hr) 84.0 14.4 AUC.sub.0-24 (.mu.g/mL hr)
844.6 188
[0288] In the animals as administered with the self-emulsifying
composition of Example 14, values of the Cmax and the AUC.sub.0-2,
which are parameters of the absorption speed, were higher than the
control group (fasted). With respect to the AUC.sub.0-2 which is in
particular a parameter of the blood concentration increase
immediately after the administration, the values in the animals as
administered with the composition of Example 14 were about six
times as high as those in the control group. The Cmax values were
about 7.3 times as high as those in the control group. On the other
hand, with respect to the AUC.sub.0-24 as a parameter of the
absorption amount, the values in the animals as administered with
the self-emulsifying composition of Example 14 were about 4.5 times
as high as those in the control group. More specifically, it was
confirmed that, when the self-emulsifying composition of Example 14
was administered, amount of the EPA absorbed until 24 hours after
the oral administration increased, and also, EPA absorption was
rapid especially after the oral administration compared to the
control group. Accordingly, the self-emulsifying composition of the
present invention would be a candidate for the self-emulsifying
preparation capable of rapidly and markedly increasing the blood
EPA concentration with rapid and effective pharmacological action
even if taken under pre-meal, pre-sleeping, or other fasting
conditions.
Test Example 6 <Pharmacokinetics in Crab-Eating Macaques>
[0289] The composition of Example 14 is orally administered to 6
crab-eating macaques (at the age of 2 to 5 years with the body
weight of 2.70 to 4.65 kg; Hamuri) under fasting conditions, and
blood EPA concentration is evaluated. The test animals are fasted
for 12 hours or more before the administration, and each animal is
administered with the self-emulsifying composition in an amount
corresponding to 45 mg/kg body weight of the EPA-E. The control
group is administered with the EPA-E stock solution encapsulated in
a capsule. Blood is collected before the administration, and 1, 2,
4, 6, 8, 10, 12, 24, 48 and 72 hours after the administration, and
plasma is separated to measure EPA in plasma by LC/MS/MS. From the
test results, the maximum blood concentration (Cmax), the area
under the blood concentration vs time curve from zero to 12 hours
(AUC.sub.0-12), and the area under the blood concentration vs time
curve from zero to 72 hours (AUC.sub.0-72) are calculated. In the
calculation of each parameter, correction is made by subtracting
the blood EPA concentration before the administration from the
measured blood concentration.
[0290] In the animals having the composition of Example 14
administered thereto, values of blood concentration parameters,
such as the Cmax and the AUC.sub.0-12, are increased as compared
with the control group. More specifically, it is confirmed that,
when the self-emulsifying composition of Example 14 is
administered, amount of the EPA absorbed is increased, and also,
EPA absorption is rapid after the oral administration.
(Example 2-1) Self-Emulsifying Capsule Preparation.
[0291] A soft gelatin capsule filled with 375 mg (amount
corresponding to 300 mg of EPA-E) of the self-emulsifying
composition as obtained in Example 14 was produced by rotary
method. The self-emulsifying capsule preparation thus produced was
identical in shape to the soft gelatin capsule as filled with EPA-E
alone, and escaped from such disadvantages as the deformation of
capsule film immediately after the production.
(Referential Example 2-2 and Comparative Example 2-3) Capsule
Preparations.
[0292] The self-emulsifying composition of the Example and the
composition of the Comparative Example were prepared and stored by
repeating the method of Example 1 so that the compositional ratios
were as shown in Table 4. Formulations of the compositions are
shown in Table 4.
[0293] A soft gelatin capsule filled with 375 mg of the composition
of Referential Example 2-1 and that filled with 441 mg of the
composition of Comparative Example 2-2 (both amounts corresponding
to 300 mg of EPA-E) were produced by rotary method. The
self-emulsifying capsule preparation thus produced was identical in
shape to the soft gelatin capsule as filled with EPA-E alone, and
escaped from such disadvantages as the deformation of capsule
film.
Test Example 6 <Capsule Hardness Retention>
[0294] The capsule preparations of Example 2-1, Referential Example
2-2 and Comparative Example 2-3 were measured in hardness. Each
preparation was also measured in hardness after the storage at
40.degree. C. and a relative humidity of 75% for one, two, and four
weeks.
[0295] The results at the initial stage and the results after the
storage at 40.degree. C. for one, two, and four weeks are shown in
Table 4. The preparation at the initial stage refers to the
preparation which has been stored at room temperature after its
production until the evaluation of the hardness. Since having been
stored at 40.degree. C. as sealed in aluminum packages, the
preparations were not affected by the moisture.
TABLE-US-00004 TABLE 4 Referential Comparative Component Ex. 2-1
Ex. 2-2 Ex. 2-3 Ethyl eicosapentaenoate 80.0 80.0 68.0 Purified
water 1.0 2.0 -- Polyoxyethylene (20) 10.0 5.8 7.1 sorbitan oleate
Sorbitan monolaurate 4.0 -- -- Polyoxyl 35 castor oil 5.0 5.8 7.1
Soybean lecithin -- 6.4 9.5 Propylene glycol -- -- 8.3 Total 100.0
100.0 100.0 Test Ex. 6 Initial 31.8 28.9 15.7 Hardness stage (kgf)
At 40.degree. C. -- -- 9.1 for 1 week At 40.degree. C. 31.1 -- 8.9
for 2 weeks At 40.degree. C. 30.8 27.4 8.1 for 4 weeks
[0296] The preparation of Example 2-1 is a capsule preparation of
the present invention, and the preparation of Referential Example
2-2 is of a formulation replacing sorbitan monolaurate contained in
Example 2-1 by soybean lecithin. The preparations had hardness
values of 31.8 kgf and 28.9 kgf, respectively, at the initial
stage, values very close to each other, and such values were
essentially not reduced even after the storage at 40.degree. C. for
one to four weeks. This indicates that neither a sorbitan fatty
acid ester nor soybean lecithin is a component causing the
reduction in hardness of a capsule.
[0297] The preparation of Comparative Example 2-3 is of a
formulation replacing water in Referential Example 2-2 by propylene
glycol. The hardness of this preparation was about 54% of that of
Referential Example 2-2, that is to say, the preparation was
inferior in hardness already at the initial stage. Moreover, the
hardness of the preparation was greatly reduced after the storage
at 40.degree. C. for only one week.
[0298] It was found from the above that, while a polyhydric alcohol
possibly comprising about 8% of the liquid content will cause the
reduction in hardness, the inventive composition that contains no
polyhydric alcohols but water does not cause the reduction in
hardness.
INDUSTRIAL APPLICABILITY
[0299] The self-emulsifying composition of the present invention is
excellent in at least one out of the compatibility (appearance),
the self-emulsifying property, the composition dispersibility, the
emulsion stability and the absorbability, and it, as being absorbed
rapidly even if taken before meals, suppresses increase of serum TG
after the meal. The self-emulsifying composition of the present
invention is useful for incorporating in various foods, or as food
for special dietary uses, food with health claims (food for
specified health use and food with nutrient function claims),
health food (supplement), or a pharmaceutical product.
[0300] The self-emulsifying composition of the present invention
has no or low content of the polyhydric alcohol, and therefore, the
composition is free from the problem of softening and deformation
of the capsule during the distribution or storage caused by the
polyhydric alcohol. In other words, the self-emulsifying
composition of the present invention is associated with reduced
risk of quality change.
[0301] The self-emulsifying composition of the present invention
has the quality as a pharmaceutical product capable of being stored
in a cold or hot location since the composition does not become
cloudy or separated even if stored in low or high temperature
environment.
* * * * *