U.S. patent application number 17/727301 was filed with the patent office on 2022-08-11 for pharmaceutical formulations for a liquid dosage form and a controlled release dosage form.
This patent application is currently assigned to INDUSTRIAL TECHNOLOGY RESEARCH INSTITUTE. The applicant listed for this patent is INDUSTRIAL TECHNOLOGY RESEARCH INSTITUTE. Invention is credited to Kuo-Kuei HUANG, Zong-Keng KUO, Tze-Chung LEE, Jia-Horng LIAW, Meng-Nan LIN, Pei-Hsin LIN, Chu-Hsun LU, I-Huang LU, I-Hong PAN, Shu-Fang WEN, Ya-Yan YANG.
Application Number | 20220249395 17/727301 |
Document ID | / |
Family ID | |
Filed Date | 2022-08-11 |
United States Patent
Application |
20220249395 |
Kind Code |
A1 |
HUANG; Kuo-Kuei ; et
al. |
August 11, 2022 |
PHARMACEUTICAL FORMULATIONS FOR A LIQUID DOSAGE FORM AND A
CONTROLLED RELEASE DOSAGE FORM
Abstract
A method for treating an autoimmune neurological disease and/or
a neurodegenerative disease is provided. The method includes
administering an effective amount of at least one compound having
Formula (I), Formula (II) or Formula (III), or its geometric
isomer, enantiomer or diastereomer to a subject in need thereof:
##STR00001## wherein is a single or double bond, X is NCH.sub.3 or
CH.sub.2, Y is null, O or N, Z is O or N, R.sub.1 is H, OH, and
R.sub.2 is null, H, C.sub.1-C.sub.8 alkyl, --(C.dbd.O)-alkyl,
--(C.dbd.O)-aryl, --(C.dbd.O)-alkyl-aryl, --(C.dbd.O)-heteroaryl,
cycloalkyl or heterocycloalkyl, which optionally substituted by one
or more of --OH, --NO.sub.2, --NH.sub.2, --NR.sub.3R.sub.4,
carbonyl, alkoxyl, alkyl or --OCF.sub.3, wherein R.sub.3 and
R.sub.4 independently are H, alkyl, O.sub.2CH.sub.3,
--(C.dbd.O)--CH.sub.3 or (C.dbd.O)--NH.sub.2.
Inventors: |
HUANG; Kuo-Kuei; (Zhubei
City, TW) ; PAN; I-Hong; (Zhubei City, TW) ;
WEN; Shu-Fang; (Hsinchu County, TW) ; LIN;
Meng-Nan; (Zhubei City, TW) ; LU; I-Huang;
(Hsinchu City, TW) ; KUO; Zong-Keng; (Hsinchu
City, TW) ; LU; Chu-Hsun; (Hsinchu City, TW) ;
LEE; Tze-Chung; (Taoyuan City, TW) ; YANG;
Ya-Yan; (Taichung County, TW) ; LIAW; Jia-Horng;
(Taipei City, TW) ; LIN; Pei-Hsin; (Hsinchu City,
TW) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
INDUSTRIAL TECHNOLOGY RESEARCH INSTITUTE |
Hsinchu |
|
TW |
|
|
Assignee: |
INDUSTRIAL TECHNOLOGY RESEARCH
INSTITUTE
Hsinchu
TW
|
Appl. No.: |
17/727301 |
Filed: |
April 22, 2022 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16023940 |
Jun 29, 2018 |
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17727301 |
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62527300 |
Jun 30, 2017 |
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International
Class: |
A61K 31/047 20060101
A61K031/047; A61K 31/215 20060101 A61K031/215; A61K 31/335 20060101
A61K031/335; A61K 9/50 20060101 A61K009/50; A61K 31/352 20060101
A61K031/352; A61K 9/00 20060101 A61K009/00; A61K 31/045 20060101
A61K031/045; A61P 37/00 20060101 A61P037/00; A61P 25/28 20060101
A61P025/28; A61K 9/08 20060101 A61K009/08; A61K 9/14 20060101
A61K009/14; A61K 31/075 20060101 A61K031/075; A61K 31/122 20060101
A61K031/122; A61K 31/222 20060101 A61K031/222; A61K 31/343 20060101
A61K031/343; A61K 47/02 20060101 A61K047/02; A61K 47/26 20060101
A61K047/26; A61K 47/34 20060101 A61K047/34; A61K 47/38 20060101
A61K047/38; A61K 47/40 20060101 A61K047/40 |
Claims
1. A pharmaceutical formulation for a liquid dosage form of at
least one compound having Formula (I), Formula (II) or Formula
(III), comprising: 0.1-30% by weight of at least one compound
having Formula (I), Formula (II) or Formula (III), or its
enantiomer, diastereomer or pharmaceutically acceptable salt;
##STR00043## wherein is a single or double bond, X is NCH.sub.3 or
CH.sub.2, Y is null, O or N, Z is O or N, R.sub.1 is H, OH, and
R.sub.2 is null, H, C.sub.1-C.sub.8 alkyl, --(C.dbd.O)-alkyl,
--(C.dbd.O)-aryl, --(C.dbd.O)-alkyl-aryl, --(C.dbd.O)-heteroaryl,
cycloalkyl or heterocycloalkyl, which optionally substituted by one
or more of --OH, --NO.sub.2, --NH.sub.2, NR.sub.3R.sub.4, carbonyl,
alkoxyl, alkyl or --OCF.sub.3, wherein R.sub.3 and R.sub.4
independently are H, alkyl, --SO.sub.2CH.sub.3,
--(C.dbd.O)--CH.sub.3 or --(C.dbd.O)--NH.sub.2; and 0.1-15% by
weight of a copolymer of poly(ethylene oxide) and poly(propylene
oxide); 0.1-60% by weight of cyclodextrin or a derivative thereof;
and 1-99% by weight of solvent, wherein the at least one compound
having Formula (I) comprises at least one compound having any one
of Formula (IV) to Formula (XVI): ##STR00044## as trans-sobrerol;
##STR00045## ##STR00046## wherein the at least one compound having
Formula (II) comprises at least one compound having Formula (XVII):
##STR00047## and wherein the at least one compound having Formula
(III) comprises at least one compound having Formula (XVIII):
##STR00048##
2. The pharmaceutical formulation for a liquid dosage form of at
least one compound having Formula (I), Formula (II) or Formula
(III) as claimed in claim 1, wherein the copolymer of poly(ethylene
oxide) and poly(propylene oxide) comprises poly(ethylene
oxide)x-poly(propylene oxide)y-poly(ethylene oxide)x (PEO-PPO-PEO),
in which, x is an integer of 30-120 and y is an integer of
10-50.
3. The pharmaceutical formulation for a liquid dosage form of at
least one compound having Formula (I), Formula (II) or Formula
(III) as claimed in claim 1, wherein the derivative of cyclodextrin
comprises 2-hydroxypropyl-beta cyclodextrin,
2-hydroxypropyl-.gamma.-cyclodextrin, .beta.-CD sulfobutyl ether
sodium salt or randomly methylated .beta.-cyclodextrin.
4. The pharmaceutical formulation for a liquid dosage form of at
least one compound having Formula (I), Formula (II) or Formula
(III) as claimed in claim 1, wherein the pharmaceutical formulation
comprises: 0.1-30% by weight of the at least one compound having
Formula (I), Formula (II) or Formula (III), or its enantiomer,
diastereomer or pharmaceutically acceptable salt; 0.1-15% by weight
of the copolymer of poly(ethylene oxide) and polypropylene oxide),
wherein the copolymer of poly(ethylene oxide) and poly(propylene
oxide) is poly(ethylene oxide)x-poly(propylene
oxide)y-poly(ethylene oxide)x (PEO-PPO-PEO), in which, x is an
integer of 76 and y is an integer of 30; and 0.1-60% by weight of
the cyclodextrin or derivative thereof, wherein the cyclodextrin or
derivative thereof is 2-hydroxypropyl-beta cyclodextrin.
5. The pharmaceutical formulation for a liquid dosage form of at
least one compound having Formula (I), Formula (II) or Formula
(III) as Formula (I) is at least one compound having Formula (IV)
as trans-sobrerol: ##STR00049##
6. The pharmaceutical formulation for a liquid dosage form of at
least one compound having Formula (I), Formula (II) or Formula
(III) as claimed in claim 5, wherein the sobrerol comprises (+)
trans-sobrerol, (-) trans-sobrerol or a combination thereof
7. The pharmaceutical formulation for a liquid dosage form of at
least one compound having Formula (I), Formula (II) or Formula
(III) as claimed in claim 5, wherein the sobrerol is (+)
trans-sobrerol.
8. The pharmaceutical formulation for a liquid dosage form of at
least one compound having Formula (I), Formula (II) or Formula
(III) as claimed in claim 5, wherein the sobrerol is (-)
trans-sobrerol.
9. The pharmaceutical formulation for a liquid dosage form of at
least one compound having Formula (I), Formula (II) or Formula
(III) as claimed in claim 5, wherein the sobrerol is a mixture of
(+) trans-sobrerol and (-) trans-sobrerol.
10. A pharmaceutical formulation for a controlled release dosage
form of at least one compound having Formula (I), Formula (II) or
Formula (III), comprising: a composition of a particle carrier; a
composition of a drug layer coated on the carrier, which comprises:
at least one compound having Formula (I), Formula, (II) or Formula
(III), or its enantiomer, diastereomer or pharmaceutically
acceptable salt; ##STR00050## wherein is a single or double bond, X
is NCH.sub.3 or CH.sub.2, Y is null, O or N, Z is O or N, R.sub.1
is H, OH, and R.sub.2 is null, H, C.sub.1-C.sub.8 alkyl,
--(C.dbd.O)-alkyl, --(C.dbd.O)-aryl, --(C.dbd.O)-alkyl-aryl,
--(C.dbd.O)-heteroaryl, cycloalkyl or heterocycloalkyl, which
optionally substituted by one or more of --OH, --NO.sub.2,
--NH.sub.2, --NR.sub.3R.sub.4, carbonyl, alkoxyl, alkyl or
--OCF.sub.3, wherein R.sub.3 and R.sub.4 independently are H,
alkyl, --SO.sub.2CH.sub.3, --(C.dbd.O)--CH.sub.3 or
--(C.dbd.O)--NH.sub.2; and at least one binder; and a composition
of a controlled release layer coated on the drug layer, wherein in
the pharmaceutical formulation for a controlled release dosage
form, the composition of a particle carrier occupies 35-98% by
weight, the composition of a drug layer occupies 1-64% by weight,
and the composition of a controlled release layer occupies 0.5-50%
by weight, wherein the at least one compound having Formula (I),
Formula (II) or Formula (III), or its enantiomer, diastereomer or
pharmaceutically acceptable salt occupies 1-99% by weight of the
composition of a drug layer, wherein the at least one compound
having Formula (I) comprises at least one compound having any one
of Formula (IV) to Formula (XVI): ##STR00051## as trans-sobrerol;
##STR00052## ##STR00053## wherein the at least one compound having
Formula (II) comprises at least one compound having Formula (XVII):
##STR00054## wherein the at least one compound having Formula (III)
comprises at least one compound having Formula (XVIII):
##STR00055##
11. The pharmaceutical formulation for a controlled release dosage
form of at least one compound having Formula (I), Formula (II) or
Formula (III) as claimed in claim 10, wherein the composition of a
particle carrier comprises microcrystalline cellulose, lactose,
corn starch, mannitol, sodium carboxymethyl cellulose, common salt,
or germanium dioxide.
12. The pharmaceutical formulation for a controlled release dosage
form of at least one compound having Formula (I), Formula (II) or
Formula (III) as claimed in claim 10, wherein the at least one
binder comprises hydroxypropyl methyl cellulose, hydroxypropyl
cellulose, polyvinyl, polyvinyl alcohol or a combination
thereof.
13. The pharmaceutical formulation for a controlled release dosage
form of at least one compound having Formula (I), Formula (II) or
Formula (III) as claimed in claim 10, wherein the composition of a
drug layer further comprises an anti-adherent and/or a
plasticizer.
14. The pharmaceutical formulation for a controlled release dosage
form of at least one compound having Formula (I), Formula (II) or
Formula (III) as claimed in claim 10, wherein the composition of a
controlled release layer comprises at least one water-insoluble
polymer or wax-like ingredient.
15. The pharmaceutical formulation for a controlled release dosage
form of at least one compound having Formula (I), Formula (II) or
Formula (III) as claimed in claim 14, wherein the at least one
water-insoluble polymer or wax-like ingredient comprises ethyl
cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose,
ethyl acrylate-methyl methacrylate-trimethyl ammonium chloride
ethyl methacrylate copolymer, methyl methacrylate-ethyl acrylate
copolymer, polyvinylpyrrlidone, polyvinyl alcohol, hydrogenated
castor oil, hydrogenated coconut oil, stearic acid, stearyl alcohol
or a combination thereof.
16. The pharmaceutical formulation for a controlled release dosage
form of at least one compound having Formula (I), Formula (II) or
Formula (III) as claimed in claim 14, wherein the composition of a
controlled release layer further comprises an anti-adherent and/or
a plasticizer.
17. The pharmaceutical formulation for a controlled release dosage
form of at least one compound having Formula (I), Formula (II) or
Formula (III) as claimed in claim 10, wherein the at least one
compound having Formula (I) is at least one compound haying Formula
(IV) as trans-sobrerol: ##STR00056##
18. The pharmaceutical formulation for a controlled release dosage
form of at least one compound having Formula (I), Formula (II) or
Formula (III) as claimed in claim 17, wherein the sobrerol
comprises (+) trans-sobrerol, (-) trans-sobrerol or a combination
thereof.
19. The pharmaceutical formulation for a controlled release dosage
form of at least one compound having Formula (I), Formula (II) or
Formula (III) as claimed in claim 17, wherein the sobrerol is (+)
trans-sobrerol.
20. The pharmaceutical formulation for a controlled release dosage
form of at least one compound having Formula (I), Formula (II) or
Formula (III) as claimed in claim 17, wherein the sobrerol is (-)
trans-sobrerol.
21. The pharmaceutical formulation for a controlled release dosage
form of at least one compound having Formula (I), Formula (II) or
Formula (III) as claimed in claim 17, wherein the sobrerol is a
mixture of (+) trans-sobrerol and (-) trans-sobrerol.
22. The pharmaceutical formulation for a controlled release dosage
form of at least one compound having Formula (I), Formula (II) or
Formula (III) as claimed in claim 17, wherein the composition of a
particle carrier comprises microcrystalline cellulose, the
composition of a drug layer comprises (-) trans-sobrerol, at least
one binder comprising hydroxypropyl methyl cellulose, and an
anti-adherent comprising talcum powder, the composition of a
controlled release layer comprises at least one water-insoluble
polymer comprising ethyl cellulose and hydroxypropyl methyl
cellulose, and an anti-adherent comprising talcum powder, and
wherein in the pharmaceutical formulation for a controlled release
dosage form, the composition of a particle carrier occupies 40-90%
by weight, the composition of a drug layer occupies 15-50% by
weight, and the composition of a controlled release layer occupies
1-15% by weight, and wherein the (-) trans-sobrerol occupies 40-90%
by weight of the composition of a drug layer.
23. The pharmaceutical formulation for a controlled release dosage
form of at least one compound having Formula (I), Formula (II) or
Formula (III) as claimed in claim 17, wherein the composition of a
particle carrier comprises microcrystalline cellulose, the
composition of a drug layer comprises (-) trans-sobrerol and at
least one binder comprising polyvinyl pyrrolidone, the composition
of a controlled release layer comprises at least one
water-insoluble polymer comprising ethyl cellulose and
hydroxypropyl methyl cellulose, and wherein the pharmaceutical
formulation for a controlled release dosage form, the composition
of a particle carrier occupies 35-95% by weight, the composition of
a drug layer occupies 5-60% by weight, and the composition of a
controlled release layer occupies 0.5-20% by weight, and wherein
the (-) trans-sobrerol occupies 40-90% by weight of the composition
of a drug layer.
24. The pharmaceutical formulation for a controlled release dosage
form of at least one compound having Formula (I), Formula (II) or
Formula (III) as claimed in claim 17, wherein the composition of a
particle carrier comprises microcrystalline cellulose, the
composition of a drug layer comprises a mixture of (+)
trans-sobrerol and (-) trans-sobrerol and at least one binder
comprising polyvinyl pyrrolidone, the composition of a controlled
release layer comprises at least one water-insoluble polymer
comprising ethyl cellulose and hydroxypropyl methyl cellulose, and
wherein in the pharmaceutical formulation for a controlled release
dosage form, the composition of a particle carrier occupies 35-95%
by weight, the composition of a drug layer occupies 5-60% by
weight, and the composition of a controlled release layer occupies
0.5-20% by weight, and wherein the mixture of (+) trans-sobrerol
and (-) trans-sobrerol occupies 40-90% by weight of the composition
of a drug layer.
25. The pharmaceutical formulation for a controlled release dosage
form of at least one compound having Formula (I), Formula (II) or
Formula (III) as claimed in claim 10, further comprising a
composition of a coating layer coated on the controlled release
layer, wherein the pharmaceutical formulation for a controlled
release dosage form, the composition of a particle carrier occupies
35-98% by weight, the composition of a drug layer occupies 1-64% by
weight, the composition of a controlled release layer occupies
1-50% by weight, and the composition of a coating layer occupies
1-35% by weight.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a Divisional of pending U.S. patent
application Ser. No. 16/023,940, filed on Jun. 29, 2018 and
entitled "METHOD FOR TREATING AN AUTOIMMUNE NEUROLOGICAL DISEASE
AND/OR NEURODEGENERATIVE DISEASE AND PHARMACEUTICAL FORMULATIONS
FOR A LIQUID DOSAGE FORM AND A CONTROLLED RELEASE DOSAGE FORM",
which claims the benefit of U.S. Provisional Application No.
62/527,300, filed on Jun. 30, 2017, the entirety of which is
incorporated by reference herein.
TECHNICAL FIELD
[0002] The technical field relates to a method for treating an
autoimmune neurological disease and/or neurodegenerative disease
and pharmaceutical formulations for a liquid dosage form and a
controlled release dosage form.
BACKGROUND
[0003] Autoimmune diseases involving the central and peripheral
nervous system are also known as autoimmune neurological
diseases.
[0004] Multiple sclerosis (MS) is a disease that causes
demyelination of spinal nerve and brain cells and is considered an
autoimmune neurological disease. Patients with multiple sclerosis
may experience a wide range of symptoms. Because of the nature of
multiple sclerosis, symptoms can vary widely from person to person.
The of multiple sclerosis may change in severity even from day to
day, while the two most common symptoms are fatigue and difficulty
walking.
[0005] Although multiple treatment options exist for autoimmune
neurological diseases and/or neurodegenerative diseases, such as
multiple sclerosis, no cure is yet available for them.
[0006] Therefore, there is need for a new therapy for autoimmune
neurological diseases and/or neurodegenerative diseases.
SUMMARY
[0007] The present disclosure provides a method for treating an
autoimmune neurological disease and/or a neurodegenerative disease.
The method comprises administering an effective amount of at least
one compound having Formula (I), Formula (II) or Formula (III), or
its geometric isomer, enantiomer, diastereomer or pharmaceutically
acceptable salt to a subject in need thereof:
##STR00002##
wherein [0008] is a single or double bond, [0009] X is NCH.sub.3 or
CH.sub.2, [0010] Y is null, O or N, [0011] Z is O or N, [0012]
R.sub.1 is H, OH, and [0013] R.sub.2 is null, H, C.sub.1-C.sub.5
alkyl, --(C.dbd.O)-alkyl, --(C.dbd.O)-aryl, --(C.dbd.O)-alkyl-aryl,
--(C.dbd.O)-heteroaryl, cycloalkyl or heterocycloalkyl, which
optionally substituted by one or more of --OH, --NO.sub.2,
--NH.sub.2, --N.sub.3R.sub.4, carbonyl, alkoxyl, alkyl or
--OCF.sub.3, wherein R.sub.3 and R.sub.4 independently are H,
alkyl, --SO.sub.2CH.sub.3, --(C.dbd.O)--CH.sub.3 or
--(C.dbd.O)-NH.sub.2.
[0014] The present disclosure also provides a pharmaceutical
formulation for a liquid dosage form of at least one compound
having Formula (I), Formula (II) or Formula (III). The
pharmaceutical formulation for a liquid dosage of at least one
compound having Formula (I), Formula (II) or Formula (III)
comprises: 0.1-30% by weight of at least one compound having
Formula (I), Formula (II) or Formula (III), or its geometric
isomer, enantiomer, diastereomer or pharmaceutically acceptable
salt:
##STR00003##
wherein [0015] is a single or double bond, [0016] X is NCH.sub.3 or
CH.sub.2, [0017] Y is null, O or N, [0018] Z is O or N, [0019]
R.sub.1 is H, OH, and [0020] R.sub.2 is null, H, C.sub.1-C.sub.8
alkyl, --(C.dbd.O)-alkyl, --(C.dbd.O)-aryl, --(C.dbd.O)-heteroaryl,
cycloalkyl or heterocycloalkyl, which optionally substituted by one
or more of --OH, --NO.sub.2, --NH.sub.2, --NR.sub.4, carbonyl,
alkoxyl, alkyl or wherein R.sub.3 and R.sub.4 independently are H,
alkyl, --SO.sub.2CH.sub.3, --(C.dbd.O)-CH.sub.3 or
--(C.dbd.O)--NH.sub.2; and 0.1-15% by weight of a copolymer of
poly(ethylene oxide) and polypropylene oxide); [0021] 0.1-60% by
weight of cyclodextrin or a derivative thereof; and [0022] 1-99% by
weight of solvent.
[0023] The present disclosure further provides a pharmaceutical
formulation for a controlled release dosage form of at least one
compound having Formula (I), Formula (II) or Formula (III). The
pharmaceutical formulation for a controlled release dosage form of
at least one compound having Formula (I), Formula (II) or Formula
(III) comprises:
a composition of a particle carrier; a composition of a drug layer
coated on the carrier, which comprises: [0024] at least one
compound having Formula (I), Formula (II) or Formula (III), or its
geometric isomer, enantiomer, diastereomer or pharmaceutically
acceptable salt:
##STR00004##
[0024] wherein [0025] is a single or double bond, [0026] X is
NCH.sub.3 or CH.sub.2, [0027] Y is null, O or N, [0028] Z is O or
N, [0029] R.sub.1 is H, OH, and [0030] R.sub.2 is null, H,
C.sub.1-C.sub.8 alkyl, --(C.dbd.O)-alkyl, --(C.dbd.O)-aryl,
--(C.dbd.O)-alkyl-aryl, --(C.dbd.O)-heteroaryl, cycloalkyl or
heterocycloalkyl, which optionally substituted by one or more of
--OH, --NO.sub.2, --NH.sub.2, --NR.sub.3R.sub.4, carbonyl, alkoxyl,
alkyl or --OCF.sub.3, wherein R.sub.3 and R.sub.4 independently are
H, alkyl, --O.sub.2CH.sub.3, --(C.dbd.O)--CH.sub.3 or
--(C.dbd.O)--NH.sub.2; and [0031] at least one binder; a
composition of a controlled release layer coated on the drug layer;
and a composition of a coating layer coated on the drug layer,
wherein in the pharmaceutical formulation for a controlled release
dosage form, the composition of a particle carrier occupies 35-98%
by weight, the composition of a drug layer occupies 1-64% by
weight, and the composition of a controlled release layer occupies
0.5-50% by weight, and wherein the at least one compound having
Formula (I), Formula (II) or Formula (III), or its geometric
isomer, enantiomer, diastereomer or pharmaceutically acceptable
salt occupies 1-99% by weight of the composition of a drug
layer.
[0032] A detailed description is given in the following embodiments
with reference to the accompanying drawings.
DESCRIPTION OF DRAWINGS
[0033] The present invention can be more fully understood by
reading the subsequent detailed description and examples with
references made to the accompanying drawings, wherein:
[0034] FIG. 1 shows the results of the dissolution testing for
controlled release particles with 17% (-)trans-sobrerol
(coated-drug carrying particles) and trans-sobrerol drug
carrying-particles (uncoated-drug carrying particles);
[0035] FIG. 2 shows the results of the dissolution testing for
controlled release particles with 20% (+)(-)trans-sobrerol
(coated-drug carrying particles) and (+)(-)trans-sobrerol drug
carrying-particles (uncoated-drug carrying particles);
[0036] FIG. 3 shows the results of the dissolution testing for
controlled release particles with 8% (+)(-)trans-sobrerol
(coated-drug carrying particles) and (+)(-)trans-sobrerol drug
carrying-particles (uncoated-drug carrying particles);
[0037] FIG. 4 shows the results of the dissolution testing for
controlled release particles with 32% (+)(-)trans-sobrerol
(coated-drug carrying particles) and (+)(-) trans-sobrerol drug
carrying-particles (uncoated-drug carrying particles)
(uncoated-drug carrying particles);
[0038] FIG. 5A shows respective EAE scores of the mice administered
with 30 mg/kg and 100 mg/kg dosages of (-) trans-sobrerol and the
mice administered with vehicle (DMSO:CrEL:saline=10:10:80), one
time a day in a therapeutic administration experiment.
Mean.+-.standard error of the mean; n=10; *: p<0.05, **:
p<0.01, as compared to the vehicle treatment group. Student's
t-test;
[0039] FIG. 5B shows respective EAE scores of the mice administered
with 50 mg/kg and 100 mg/kg dosages of (-) trans-sobrerol, and the
mice administered with vehicle (DMSO:CrEL:saline=10:10:80), two
times a day in a therapeutic experiment. BID: two times a day (Bi
in die). Mean.+-.standard error of the mean; n=10; *: p<0.05,
**: p<0.01, ***: p<0.001, as compared to the vehicle
treatment group. Student's t-test;
[0040] FIG. 5C shows respective EAE scores of the mice administered
with 10 mg/kg, 25 mg/kg, 50 mg/kg and 100 mg/kg dosages of (-)
trans-sobrerol, the mice administered with vehicle
(DMSO:CrEL:saline=10:10:80), three times a day, and the mice
administered with 100 mg/kg dosage of dimethyl fumarate, two times
a day in a therapeutic administration experiment. BID (Bi in die):
two times a day; TLD (Ter in die): three times a day.
Mean.+-.standard error of the mean; n-10; *p<0.05, **:
p<0.01, ***: p<0.001, as compared to the vehicle treatment
group. Student's t-test;
[0041] FIG. 6A shows Hematoxylin and eosin stain for the spinal
cords of the mice treated. with 100 mg/kg dosages of (-)
trans-sobrerol three times a day in a therapeutic administration
experiment;
[0042] FIG. 6B shows Hematoxylin and eosin stain for the spinal
cords of the mice treated with vehicle three times a day in a
therapeutic administration experiment. Demyelination is indicated
by the arrows;
[0043] FIG. 6C shows Luxol fast blue stain for the spinal cords of
the mice treated with treated with 100 mg/kg dosages of (-)
trans-sobrerol three times a day in a therapeutic administration
experiment;
[0044] FIG. 6D shows Luxol fast blue stain for the spinal cords of
the mice treated with vehicle three times a day in a therapeutic
administration experiment. Demyelination is indicated by the
arrows;
[0045] FIG. 7A shows demyelination scores of spinal cords of the
mice with 100 mg/kg dosages of (-) trans-sobrerol three times a
day, the mice treated with vehicle three times a day, and the mice
without any treatment in a therapeutic administration experiment.
TID (Ter in die): three times a day. Mean.+-.standard error of the
mean; n=10; ***: p<0.001, as compared to the vehicle treatment
group. Student's t-test;
[0046] FIG. 7B shows axonal swelling scores of spinal cords of the
mice with 100 mg/kg dosages of (-) trans-sobrerol three times a
day, the mice treated with vehicle three times a day, and the mice
without any treatment in a therapeutic administration experiment.
TID (Ter in die): three times a day. Mean.+-.standard error of the
mean; n=10; **: P<0.01, ***: p<0.001, as compared to the
vehicle treatment group. Student's t-test;
[0047] FIG. 7C shows inflammation scores of spinal cords of the
mice with 100 mg/kg dosages of (-) trans-sobrerol three times a
day, the mice treated with vehicle three times a day, and the mice
without any treatment in a therapeutic administration experiment.
TID (Ter in die): three times a day, Mean.+-.standard error of the
mean; n=10; **: p<0,01, ***: p<0.001; as compared to the
vehicle treatment group. Student's t-test;
[0048] FIG. 7D shows gliosis scores of spinal cords of the mice
with 100 mg/kg dosages of (-) trans-sobrerol three times a day, the
mice treated with vehicle three times a day, and the mice without
any treatment in a therapeutic administration experiment. TID (Ter
in die): three times a day. Mean.+-.standard error of the mean;
n=10; ***: p<0.001, as compared to the vehicle treatment group.
Student's t-test;
[0049] FIG. 8A shows respective EAE scores of the mice administered
with 100 mg/kg dosage of the mixture of (+) trans-sobrerol and (-)
trans-sobrerol and the mice administered with vehicle
(DMSO:CrEL:saline=10:10:80), one time a day in a therapeutic
administration experiment. Mean .+-.standard error of the mean;
n=10; *: p<0.05, **: <0.01, as compared to the vehicle
treatment group. Student's t-test;
[0050] FIG. 8B shows respective EAE scores of the mice administered
with 15 mg/kg, 50 mg/kg and 100 mg/kg dosages of the mixture of (+)
trans-sobrerol and (-) trans-sobrerol and the mice administered
with vehicle (DMSO:CrEL:saline=10:10:80), two times a day in a
therapeutic administration experiment. BID (Bi in die): two times a
day. Mean.+-.standard error of the mean; n=10; *p<0.05,
**:p<0.01, as compared to the vehicle treatment group. Student's
t-test;
[0051] FIG. 9A shows respective EAE scores of the mice administered
with 150 mg/kg dosage of the liquid dosage form of (-)
trans-sobrerol prepared two times a day and 300 mg/kg dosage of the
liquid dosage form of (-) trans-sobrerol prepared one time a day,
the mice administered with 100 mg/kg dosage of (-) trans-sobrerol
three times a day, and the mice administered with vehicle (6%
PEO-PPO-PEO and 40% 2-hydroxypropyl-beta cyclodextrin (%: mg/100
.mu.l water)) two times a day and vehicle
(DMSO:CrEL:saline=10:10:80) three times a day in a therapeutic
administration experiment, BID (Bi in die): two times a day; TID
(Ter in die): three times a day; QD (quaque die): one time a day.
Mean .+-.standard error of the mean; n=10; *: p<0.05, **:
p<0.01, ***: p<0.001, as compared to the vehicle treatment
group. Student's t-test;
[0052] FIG. 9B shows respective EAE scores at Day 15 after EAE
sings onset of the mice administered with 150 mg/kg dosage of the
liquid dosage form of (-) trans-sobrerol prepared two times a day
and 300 mg/kg dosage of the liquid dosage form of (-)
trans-sobrerol prepared one time a day, the mice administered with
100 mg/kg dosage of (-) trans-sobrerol three times a day, and the
mice administered with vehicle (6% PEO-PPO-PEO and 40%
2-hydroxypropyl-beta cyclodextrin (%: mg/100 .mu.l water)) two
times a day and vehicle (DMSO:CrEL:saline=10:10:80) three times a
day in a therapeutic administration experiment. BID (Bi in die):
two times a day; TID (Ter in die): three times a day; QD (quaque
die): one time a day. Mean.+-.standard error of the mean; n=10; ##:
p<0.01, ***: p<0.001, as compared to the vehicle treatment
group. Student's t-test
[0053] FIG. 10 shows respective EAE scores of the mice administered
with 100 mg/kg dosages of (-) trans-sobrerol, the mice administered
with vehicle (DMSO:CrEL:saline=10:10:80), and mice administered
with 50 mg/kg dosages of dimethyl fumarate, one time a day in a
prophylaxis administration. Mean.+-.standard error of the mean;
n=10; *: p<0.05, **: p<0.01, ***: p<0.001, as compared to
the vehicle treatment group. Student's t-test.
DETAILED DESCRIPTION
[0054] In the following detailed description, for purposes of
explanation, numerous specific details are set forth in order to
provide a thorough understanding of the disclosed embodiments. It
will be apparent, however, that one or snore embodiments may be
practiced without these specific details. In other instances,
weft-known structures and devices are schematically shown in order
to simplify the drawing.
[0055] The present disclosure provides a method for treating an
autoimmune neurological disease and/or a neurodegenerative disease.
The method for treating an autoimmune neurological disease and/or a
neurodegenerative disease may comprise, but is not limited to,
administering an effective amount of at least one compound having
Formula (I), Formula (II) or Formula (III), or its geometric
isomer, enantiomer, diastereomer or pharmaceutically acceptable
salt to a subject in need thereof:
##STR00005##
wherein [0056] may be a single or double bond, [0057] X may be
NCH.sub.3 or CH.sub.2, [0058] Y may be null, O or N, [0059] Z may
be O or N, [0060] R.sub.1 may be H, OH, and [0061] R.sub.2 may be
null, H, C.sub.1-C.sub.8 alkyl, --(C.dbd.O)-allyl,
--(C.dbd.O))-aryl, --(C.dbd.O)-alkyl-aryl, --(C.dbd.O)-heteroaryl,
cycloalkyl or heterocycloalkyl, which optionally substituted by one
or more of --OH, --NO.sub.2, --NH.sub.2, --NR.sub.3R.sub.4,
carbonyl alkoxyl, alkyl or --OCF.sub.3, wherein R.sub.3 and R.sub.4
independently are H, alkyl, --SO.sub.2CH.sub.3,
--(C.dbd.O)--CH.sub.3 or --(C.dbd.O)--NH.sub.2.
[0062] In one embodiment, in the above Formula (I), Formula (II) or
Formula (III), X may be NCH.sub.3 or CH.sub.2, Y may be null, O or
N, R.sub.1 may be H, OH, and R.sub.2 may be null, H, Me,
C.sub.2H.sub.5, C.sub.3H.sub.7, C.sub.4H.sub.4, C.sub.7H.sub.7,
COCH.sub.3, COC.sub.2H.sub.5, COC.sub.3H.sub.7, COC.sub.4H.sub.9,
COC.sub.5H.sub.11, COC.sub.6H.sub.5, COCH.sub.2C.sub.6H.sub.5,
COC.sub.2H.sub.4C.sub.6H.sub.5, COC.sub.6H.sub.4NO.sub.2, or
COC.sub.6H.sub.4OH, but they are not limited thereto.
[0063] The autoimmune neurological diseases mentioned above may
comprise multiple sclerosis, Neuromyelitis optica, Lambert-Eaton
myasthenic syndrome, autoimmune inner ear disease, narcolepsy,
neuromyotonia, Guillain-Barre syndrome, myasthenia gravis, systemic
lupus erythematosus, transverse myelitis or acute disseminated
encephalomyelitis, but it is not limited thereto. Moreover,
examples of the neurodegenerative diseases mentioned above may
comprise, but are not limited to Alzheimer's disease, Huntington's
disease, Parkinson's disease, Schizophrenia, depression,
Amyotrophic lateral sclerosis, multi-infarct dementia, motor neuron
disease or neurofibromatosis, but it is not limited thereto. In one
embodiment, the autoimmune neurological disease and/or
neurodegenerative disease mentioned above may be multiple sclerosis
(MS).
[0064] The term "an effective amount" used herein means an amount
of a compound or a drug which will have a therapeutic effect, or an
amount of a compound or a drug that is sufficient to achieve the
desired clinical improvement.
[0065] Examples of a compound having Formula (I) shown above may
comprise compounds having any one of Formula (IV) to Formula (XVI),
but they are not limited thereto:
##STR00006## ##STR00007##
[0066] Furthermore, examples of a compound having Formula (II)
shown above may comprise compounds having Formula (XVII), but they
are not limited thereto:
##STR00008##
[0067] In addition, examples of a compound having Formula (III)
shown above may comprise compounds having Formula (XVIII), but they
are not limited thereto:
##STR00009##
[0068] In one embodiment, for the method for treating an autoimmune
neurological disease and/or a neurodegenerative disease, the at
least one compound having Formula (I), Formula (II) or Formula
(III), or its geometric isomer, enantiomer, diastereomer or
pharmaceutically acceptable salt mentioned above may be at least
one compound having Formula (IV), and may be sobrerol. The sobrerol
may comprise, but is not limited to, (+) trans-sobrerol, (-)
trans-sobrerol, (+) cis-sobrerol, (-) cis-sobrerol or a combination
thereof.
[0069] In the foregoing embodiment in which the at least one
compound having Formula (I), Formula (II) or Formula (III), or its
geometric isomer, enantiomer, diastereomer or pharmaceutically
acceptable salt mentioned above may be at least one compound having
Formula (IV) shown above, and may be sobrerol, for one specific
embodiment, the sobrerol may be (+) trans-sobrerol, for another
specific embodiment, the sobrerol may be (-) trans-sobrerol, and
for yet another specific embodiment, the sobrerol may be a mixture
of (+) trans-sobrerol and (-) trans-sobrerol.
[0070] For the method for treating an autoimmune neurological
disease and/or a neurodegenerative disease, in the foregoing
embodiment in which the at least one compound having Formula (II)
or Formula (III), or its geometric isomer, enantiomer, diastereomer
or pharmaceutically acceptable salt mentioned above may be at least
one compound having Formula (IV), and may be sobrerol, the
autoimmune neurological disease and/or a neurodegenerative disease
may be multiple sclerosis, but it is not limited thereto.
[0071] In another embodiment, for the method for treating an
autoimmune neurological disease and/or a neurodegenerative disease,
the at least one compound having Formula (I), Formula (II) or
Formula (III), or its geometric isomer, enantiomer, diastereomer or
pharmaceutically acceptable salt mentioned above may have any one
of Formula (V) to Formula (XVIII) shown above. In one specific
embodiment, for the method for treating an autoimmune neurological
disease and/or a neurodegenerative disease, the at least one
compound having Formula (I), Formula (II) or Formula (III), or its
geometric isomer, enantiomer, diastereomer or pharmaceutically
acceptable salt mentioned above may be at least one compound having
Formula (I) and have any one of Formula (V) to Formula (XVI) shown
above. In another specific embodiment, for the method for treating
an autoimmune neurological disease and/or a neurodegenerative
disease, the at least one compound having Formula (I), Formula (II)
or Formula (III), or its geometric isomer, enantiomer, diastereomer
or pharmaceutically acceptable salt mentioned above may be at least
one compound having Formula (II) and have Formula (XVII) shown
above. In yet another specific embodiment, for the method for
treating an autoimmune neurological disease and/or a
neurodegenerative disease, the at least one compound having Formula
(I), Formula (II) or Formula (III), or its geometric isomer,
enantiomer, diastereomer or pharmaceutically acceptable salt
mentioned above may be at least one compound having Formula (III)
and have Formula (XVIII) shown above.
[0072] In any of the above-mentioned methods for treating an
autoimmune neurological disease and/or a neurodegenerative disease,
the subject may include, but is not limited to, a vertebrate.
Moreover, the vertebrate mentioned above may include a fish, an
amphibian, a reptile, a bird, or a mammal, but it is not limited
thereto. Examples of mammals include, but are not limited to, a
human, an orangutan, a monkey, a horse, a donkey, a dog, a cat, a
rabbit, a guinea pig, a rat, and a mouse. In one embodiment, in any
of the above-mentioned methods for treating an autoimmune
neurological disease and/or a neurodegenerative disease of the
present disclosure, the subject is a human.
[0073] Furthermore, the present disclosure also provides a novel
pharmaceutical formulation for a liquid dosage form of at least one
compound having Formula (I) or Formula (II).
##STR00010##
wherein may be a single or double bond, X may be NCH.sub.3 or
CH.sub.2, Y may be null, O or N,
Z may be O or N, R.sub.1 may be H, OH, and
[0074] R.sub.2 may be null, H, C.sub.1-C.sub.8 alkyl, --(C.dbd.O)
alkyl, --(C.dbd.O)-aryl, --(C.dbd.O)-alkyl-aryl,
--(C.dbd.O)-heteroaryl, cycloalkyl or heterocycloalkyl, which
optionally substituted by one or more of --OH, --NO.sub.2,
--NH.sub.2, --NR.sub.3R.sub.4, carbonyl, alkoxyl, alkyl or
--OCF.sub.3, wherein R.sub.3 and R.sub.4 independently are H,
alkyl, --SO.sub.2CH.sub.3, --(C.dbd.O)--CH.sub.3 or
--(C.dbd.O)--NH.sub.2.
[0075] In one embodiment, in the above Formula (I), Formula (II) or
Formula (III), X may be NCH.sub.3 or CH.sub.2, Y may be null, O or
N, R.sub.1 may be H, OH, and R.sub.2 may be null, H, Me,
C.sub.2H.sub.5, C.sub.3H.sub.7, C.sub.4H.sub.9, C.sub.7H.sub.7,
COCH.sub.3, COC.sub.2H.sub.5, COC.sub.3H.sub.7, COC.sub.4H.sub.9,
COC.sub.5H.sub.11, COC.sub.6H.sub.5, COCH.sub.2C.sub.6H.sub.5,
COC.sub.2H.sub.4C.sub.6H.sub.5, COC.sub.6H.sub.4NO.sub.2, or
COC.sub.6H.sub.4OH, but they are not limited thereto.
[0076] The foregoing pharmaceutical formulation for a liquid dosage
of at least one compound having Formula (I), Formula (II) or
Formula (III) shown above may comprise, but is not limited to, at
least one compound having Formula (I), Formula (II) or Formula
(III), or its geometric isomer, enantiomer, diastereomer or
pharmaceutically acceptable salt, a copolymer of polyethylene
oxide) and poly(propylene oxide), cyclodextrin or a derivative
thereof and a solvent.
[0077] In the pharmaceutical formulation for a liquid dosage form
of at least one compound having Formula (I), Formula (II) or
Formula (Ill) of the present disclosure mentioned above, the at
least one compound having Formula (I), Formula (II) or Formula
(III), or its geometric isomer, enantiomer, diastereomer or
pharmaceutically acceptable salt may occupy about 0.1-30% by
weight, such as about 0.1-10%, about 5-25%, about 10-20% or about
20-30% by weight, but it is not limited thereto.
[0078] Examples of a compound having Formula (I) may be the same as
those recited in the paragraphs above related to the method for
treating an autoimmune neurological disease and/or a
neurodegenerative disease of the present disclosure, and are not
repeated herein to avoid redundancy.
[0079] Similarly, examples of a compound having Formula (II) and
examples of a compound having Formula (III) may be the same as
those recited in the paragraphs above related to the method for
treating an autoimmune neurological disease and/or a
neurodegenerative disease of the present disclosure, and are not
repeated herein to avoid redundancy.
[0080] Moreover, in the pharmaceutical formulation for a liquid
dosage form of at least one compound having Formula (I) or Formula
(II) of the present disclosure mentioned above, the copolymer of
poly(ethylene oxide) and poly(propylene oxide) may occupy about
0.1-15% by weight, such as about 0.1-5%, about 0.5-12%, about 5-10%
or about 10-15% by weight, but it is not limited thereto.
[0081] Examples of the copolymer of poly(ethylene oxide) and
poly(propylene oxide) may comprise, but are not limited to
poly(ethylene oxide)x-polypropylene oxide)y-poly(ethylene oxide)x
(PEO-PPO-PEO). For the poly(ethylene oxide)x-polypropylene
oxide)y-poly(ethylene oxide)x, x may be an integer of about 30-120,
such as about 30-60, about 40-100, about 60-120 while y may be an
integer of about 10-50, such as about 10-25, about 20-40, about
25-50, but they are not limited thereto.
[0082] Furthermore, in the pharmaceutical formulation for a liquid
dosage form of at least one compound having Formula (I), Formula
(II) or Formula (III) of the present disclosure mentioned above,
the cyclodextrin or a derivative thereof may occupy about 0.1-60%
by weight, such as about 0.1-20%, about 1-50%, about 5-40%, about
20-40% or about 40-60% by weight, but it is not limited
thereto.
[0083] The derivative of cyclodextrin may comprise
2-hydroxypropyl-beta cyclodextrin,
2-hydroxypropyl-.gamma.-cyclodextrin, .beta.-CD sulfobutyl ether
sodium salt or randomly methylated .beta.-cyclodextrin, etc., but
it is not limited thereto.
[0084] In addition, in the pharmaceutical formulation for a liquid
dosage form of at least one compound having Formula (I), Formula
(II) or Formula (III) of the present disclosure mentioned above,
the solvent may occupy about 1-99% by weight, such as about 1-30%,
about 10-85%, about 20-70%, about 30-60% or about 60-99% by weight,
but it is not limited thereto.
[0085] The solvent suitable for the pharmaceutical formulation for
a liquid dosage form of at least one compound having Formula (I),
Formula (II) or Formula (III) of the present disclosure may
comprise, but is not limited to, water, ethanol, etc.
[0086] In one embodiment, in the pharmaceutical formulation for a
liquid dosage form of at least one compound having Formula (I),
Formula (II) or Formula (III) of the present disclosure mentioned
above, the at least one compound having Formula (I), Formula (II)
or Formula (III), or its geometric isomer, enantiomer, diastereomer
or pharmaceutically acceptable salt may occupy about 0.1-30% by
weight, the copolymer of poly(ethylene oxide) and poly(propylene
oxide) may occupy about 0.1-15% by weight, the cyclodextrin or a
derivative thereof may occupy about 0.1-60% by weight, and the
solvent may occupy about 1-99% by weight.
[0087] Moreover, in one embodiment, in the pharmaceutical
formulation for a liquid dosage form of at least one compound
having Formula (I), Formula (II) or Formula (III) of the present
disclosure mentioned above, the at least one compound having
Formula (I), Formula (II) or Formula (III), or its geometric
isomer, enantiomer, diastereomer or pharmaceutically acceptable
salt may occupy about 0.1-30% by weight, the copolymer of
poly(ethylene oxide) and polypropylene oxide) may occupy about
0.1-15% by weight, the cyclodextrin or a derivative thereof may
occupy about 0.1-60% by weight, and the solvent may occupy about
1-99% by weight, wherein the copolymer of poly(ethylene oxide) and
poly(propylene oxide) may be poly(ethylene oxide)x-poly(propylene
oxide)y-poly(ethylene oxide)x, in which, x is an integer of 76 and
y is an integer of 30, and wherein the cyclodextrin or derivative
thereof may be 2-hydroxypropyl-beta cyclodextrin. For this
embodiment, the at least one compound having Formula (I), Formula
(II) or Formula (III) may have Formula (IV), and may be sobrerol,
but it is not limited thereto.
[0088] Furthermore, in the of embodiment mentioned above, the
foregoing sobrerol may comprise (+) trans-sobrerol, (-)
trans-sobrerol, (+) cis-sobrerol, (-) cis-sobrerol, or a
combination thereof, but it is not limited thereto. In one specific
embodiment, the sobrerol is (+) trans-sobrerol. In another specific
embodiment, the sobrerol is trans-sobrerol. In yet another
embodiment, the sobrerol is a mixture of (+) trans-sobrerol and (-)
trans-sobrerol.
[0089] In another embodiment, for the pharmaceutical formulation
for a liquid dosage form of at least one compound having Formula
(I), Formula (II) or Formula (III) of the present disclosure, the
at least one compound having Formula (I), Formula (II) or Formula
(III), or its geometric isomer, enantiomer, diastereomer or
pharmaceutically acceptable salt mentioned above may have any one
of Formula (V) to Formula (XVIII) shown above. In one specific
embodiment, for the pharmaceutical formulation for a liquid dosage
form of at least one compound having Formula (I), Formula (II) or
Formula (III) of the present disclosure, the at least one compound
having Formula (I), Formula (II) or Formula (III), or its geometric
isomer, enantiomer, diastereomer or pharmaceutically acceptable
salt mentioned above may be at least one compound having Formula
(I) and have any one of Formula (V) to Formula (XVI) shown above.
In another specific embodiment, for the pharmaceutical formulation
for a liquid dosage form of at least one compound having Formula
(I), Formula (II) or Formula (III) of the present disclosure, the
at least one compound having Formula (I), Formula (II) or Formula
(III), or its geometric isomer, enantiomer, diastereomer or
pharmaceutically acceptable salt mentioned above may be at least
one compound having Formula (II) and have Formula (XVII) shown
above. In yet another specific embodiment, for the pharmaceutical
formulation for a liquid dosage form of at least one compound
having Formula (I), Formula (II) or Formula (III) of the present
disclosure, the at least one compound having Formula (I), Formula
(II) or Formula (III), or its geometric isomer, enantiomer,
diastereomer or pharmaceutically acceptable salt mentioned above
may be at least one compound having Formula (III) and have Formula
(XVIII) shown above.
[0090] Any foregoing pharmaceutical formulation for a liquid dosage
form of at least one compound having Formula (I), Formula (II) or
Formula (III) is capable of decreasing a dosage and/or dosing
frequency to a subject in need of being administered at least one
compound having Formula (I), Formula (II) or Formula (III), or its
geometric isomer, enantiomer, diastereomer or pharmaceutically
acceptable salt.
[0091] The subject in need of being administered at least one
compound having Formula (I), Formula (II) or Formula (III), or its
geometric isomer, enantiomer, diastereomer or pharmaceutically
acceptable salt may comprise a subject suffering from a disease
which can be treated by at least one compound having Formula (I),
Formula (II) or Formula (III) or its geometric isomer, enantiomer,
diastereomer or pharmaceutically acceptable salt, but it is not
limited thereto. In one embodiment, the disease may comprise, but
is not limited to, an autoimmune neurological disease and/or a
neurodegenerative disease. In one specific embodiment, the disease
may be multiple sclerosis.
[0092] In addition, the foregoing subject may include, but is not
limited to, a vertebrate. The vertebrate mentioned above may
include a fish, an amphibian, a reptile, a bird, or a mammal, but
it is not limited thereto. Examples of mammals include, but are not
limited to, a human, an orangutan, a monkey, a horse, a donkey, a
dog, a cat, a rabbit, a guinea pig, a rat, and a mouse. In one
embodiment, the subject is a human.
[0093] Also, the present disclosure further provides a novel
pharmaceutical formulation for a controlled release dosage form of
at least one compound having Formula (I), Formula (II) or Formula
(III) shown in the following.
##STR00011##
wherein may be a single or double bond, X may be NCH.sub.3 or
CH.sub.2, Y may be null, O or N,
Z may be O or N,
R.sub.1 may be H, OH, and
[0094] R.sub.2 may be null, H, C.sub.1-C.sub.8 alkyl,
--(C.dbd.O)-alkyl, --(C.dbd.O)-aryl, --(C.dbd.O)-alkyl-aryl,
--(C.dbd.O)-heteroaryl, cycloalkyl or heterocycloalkyl, which
optionally substituted by one or more, of --OH, --NO.sub.2,
--NH.sub.2, --NR.sub.3R.sub.4, carbonyl, alkoxyl, alkyl or
--OCF.sub.3, wherein R.sub.3 and R.sub.4 independently are H,
alkyl, --SO.sub.2CH.sub.3, --(C.dbd.O)--CH.sub.3 or
--(C.dbd.O)--NH.sub.2.
[0095] In one embodiment, in the above Formula (I), Formula (II) or
Formula (III), X nay be NCH.sub.3 or CH.sub.2, Y may be null, O or
N, R.sub.1 may be H, OH, and R.sub.2 may be null, H, Me,
C.sub.2H.sub.5, C.sub.3H.sub.7, C.sub.4H.sub.4, C.sub.7H.sub.7,
COCH.sub.3, COC.sub.2H.sub.5, COC.sub.3H.sub.7, COC.sub.4H.sub.9,
COC.sub.5H.sub.11, COC.sub.6H.sub.5, COCH.sub.2C.sub.6H.sub.5,
COC.sub.2H.sub.4C.sub.6H.sub.5, COC.sub.6H.sub.4NO.sub.2, or
COC.sub.6H.sub.4OH, but they are not limited thereto.
[0096] The foregoing pharmaceutical formulation for a controlled
release dosage form of at least one compound having Formula (I),
Formula (II) or Formula (III) shown above may comprise a
composition of a particle carrier, a composition of a drug layer
comprising at least one compound having Formula (I), Formula (II)
or Formula (III), or its geometric isomer, enantiomer, diastereomer
or pharmaceutically acceptable salt and at least one hinder, and a
composition of a controlled release layer, but it is not limited
thereto. For the controlled release dosage form of at least one
compound having Formula (I), Formula (II) or Formula (III)
mentioned above, the drug layer is coated on the particle carrier
while the controlled release layer is coated on the drug layer.
[0097] In the pharmaceutical formulation for a controlled release
dosage form of at least one compound haying Formula (I), Formula
(II) or Formula (III) of the present disclosure mentioned above,
the composition of a particle carrier may occupy about 35-98% by
weight, such as about 30-60%, about 40-90%, about 35-95%, about
50-85% by weight, but it is not limited thereto.
[0098] The composition of a particle carrier mentioned above may
comprise microcrystalline cellulose, lactose, corn starch,
mannitol, sodium carboxymethyl cellulose, common salt, germanium
dioxide, combinations thereof, etc., but it is not limited thereto.
The particle size of the particle carrier may be about 100-1300
.mu.m, such as about 200-1000 .mu.m, about 500-710 .mu.m, but it is
not limited thereto.
[0099] Moreover, in the pharmaceutical formulation for a controlled
release dosage form of at least one compound having Formula (I),
Formula (II) or Formula (III) of the present disclosure mentioned
above, the composition of a drug layer may occupy about 1-64% by
weight, such as about 5-60%, about 15-50%, about 8-32 by weight,
but it is not limited thereto. Furthermore, the at least one
compound having Formula (I), Formula (II) or Formula (III), or its
geometric isomer, enantiomer, diastereomer or pharmaceutically
acceptable salt may occupy 1-99% by weight, such as about 5-50%,
about 20-80%, about 40-90% by weight of the foregoing composition
of a drug layer.
[0100] Examples of a compound having Formula (I) may be the same as
those recited in the paragraphs above related to the method for
treating an autoimmune neurological disease and/or a
neurodegenerative disease of the present disclosure, and are not
repeated herein to avoid redundancy.
[0101] Similarly, examples of a compound having Formula (II) may be
the same as those recited in the paragraphs above related to the
method for treating an autoimmune neurological disease and/or a
neurodegenerative disease of the present disclosure, and are not
repeated herein to avoid redundancy.
[0102] The least one binder in the composition of a drug layer
mentioned above may comprise hydroxypropyl methyl cellulose,
hydroxypropyl cellulose, polyvinyl, polyvinyl alcohol or a
combination thereof, but it is not limited thereto.
[0103] In one embodiment, for the pharmaceutical formulation for a
controlled release dosage form of at least one compound having
Formula (I) or Formula (II) of the present disclosure, the
composition of a drug layer mentioned above may further comprise,
but is not limited to, an anti-adherent, a plasticizer, another
excipient, or a combination thereof.
[0104] Examples of the anti-adherent suitable for the composition
of a drug layer mentioned above may comprise, but is not limited
to, talc powder, stearic acid, stearate or colloidal silicon
dioxide, but they are not limited thereto.
[0105] The plasticizer suitable for the composition of a drug layer
mentioned above may comprise triethyl citrate, tributyl citrate,
polyethylene glycol, etc., but it is not limited thereto.
[0106] Other excipients suitable for the composition of a drug
layer mentioned above may comprise, but are not limited to lactose,
starch, mannitol, pigments, microcrystalline cellulose, castor oil,
etc.
[0107] In the composition of a drug layer mentioned above, the
content of the at least binder, the content of the anti-adherent,
the content of the plasticizer and/or the contents of other
excipients have no specific limitations, and can be adjusted
according the content of the least one compound having Formula (I),
Formula (II) or Formula (III), or its geometric isomer, enantiomer,
diastereomer or pharmaceutically acceptable salt and/or can be
adjusted as needed.
[0108] Furthermore, the composition of a controlled release layer
mentioned above may comprise at least one water-insoluble polymer
or wax-like ingredient, but it is not limited thereto. Moreover, in
the pharmaceutical formulation for a controlled release dosage form
of at least one compound having Formula (I), Formula (II) or
Formula (III) of the present disclosure mentioned above, the
composition of a controlled release layer may occupy about 0.5-50%
by weight, such as about 1-50%, about 0.5-20%, about 5-40 by
weight, but it is not limited thereto.
[0109] The at least one water-insoluble polymer or wax-like
ingredient mentioned above may comprise, but is not limited to
ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl
cellulose, ethyl acrylate-methyl methacrylate-trimethyl ammonium
chloride ethyl methacrylate copolymer, methyl methacrylate-ethyl
acrylate copolymer, polyvinylpyrrlidone, polyvinyl alcohol,
hydrogenated castor oil, hydrogenated coconut oil, stearic acid,
stearyl alcohol or a combination thereof.
[0110] In one embodiment, for the pharmaceutical formulation for a
controlled release dosage form of at least one compound having
Formula (I), Formula (II) or Formula (III) of the present
disclosure, the composition of a controlled release layer mentioned
above may further comprise an anti-adherent, a plasticizer, other
excipients or a combination thereof, but it is not limited
thereto.
[0111] The anti-adherent suitable for the composition of a
controlled release layer mentioned above may comprise, but is not
limited to, talc powder, stearic acid, stearate or colloidal
silicon dioxide.
[0112] The plasticizer suitable for the composition of a controlled
release layer mentioned above may comprise triethyl citrate,
tributyl citrate, polyethylene glycol, etc., but it is not limited
thereto.
[0113] Other excipients suitable for the composition of a
controlled release layer mentioned above may comprise, but are not
limited to lactose, starch, mannitol, pigments, microcrystalline
cellulose, castor oil, etc.
[0114] In the composition of a controlled release layer mentioned
above, the content of the anti-adherent, the content of the
plasticizer and/or the content of other excipients has no specific
limitations, and can be adjusted according the content of at least
one water-insoluble polymer and/or can be adjusted as needed.
[0115] In one embodiment, for the pharmaceutical formulation for a
controlled release dosage form of at least one compound having
Formula (I), Formula (II) or Formula (III) of the present
disclosure, the composition of a particle carrier may occupy about
35-98% by weight, the composition of a drug layer may occupy about
1-64% by weight, and the composition of a controlled release layer
may occupy about 0.5-50% by weight, wherein the at least one
compound having Formula (I), Formula (II) or Formula (III), or its
geometric isomer, enantiomer, diastereomer or pharmaceutically
acceptable salt may occupy about 1-99% by weight of the composition
of a drug layer. For this embodiment, the at least one compound
having Formula (I), Formula (II) or Formula (III) may have Formula
(IV), and may be sobrerol, but it is not limited thereto.
[0116] Moreover, in this embodiment, the foregoing sobrerol may
comprise (+) trans-sobrerol, (-) trans-sobrerol, (+) cis-sobrerol,
(-) cis-sobrerol, or a combination thereof, but it is not limited
thereto. In one specific embodiment, the sobrerol is (+)
trans-sobrerol. In another specific embodiment, the sobrerol is (-)
bans-sobrerol. In yet another embodiment, the sobrerol is a mixture
of (+) trans-sobrerol and (-) trans-sobrerol.
[0117] Alternatively, in this embodiment, the composition of a
particle carrier may comprise microcrystalline cellulose, the
composition of a drug layer may comprise (-) trans-sobrerol, at
least one binder comprising hydroxypropyl methyl cellulose, and an
anti-adherent comprising talcum powder, and the composition of a
controlled release layer may comprise at least one water-insoluble
polymer comprising ethyl cellulose and hydroxypropyl methyl
cellulose, and an anti-adherent comprising talcum powder. Moreover,
the composition of a particle carrier may occupy about 40-90% by
weight, the composition of a drug layer may occupy about 15-50% by
weight, and the composition of a controlled release layer may
occupy about 1-15% by weight, and the (-) trans-sobrerol may occupy
about 40-90% by weight of the composition of a drug layer.
[0118] Or, in this embodiment, the composition of a particle
carrier may comprise microcrystalline cellulose, the composition of
a drug layer comprises (-) trans-sobrerol and at least one binder
comprising polyvinyl pyrrolidone, the composition of a controlled
release layer comprises at least one water-insoluble polymer
comprising. ethyl cellulose and hydroxypropyl methyl cellulose. In
addition, the composition of a particle carrier may occupy about
5-60% by weight, the composition of a drug layer may occupy about
35-95% by weight, and the composition of a controlled release layer
may occupy about 0.5-20% by weight wherein the (-) trans-sobrerol
may occupy about 40-90% by weight of the composition of a drug
layer.
[0119] Or, in this embodiment, the composition of a particle
carrier may comprise microcrystalline cellulose, the composition of
a drug layer may comprise a mixture of (+) trans-sobrerol and (-)
trans-sobrerol and at least one binder comprising polyvinyl
pyrrolidone, the composition of a controlled release layer may
comprise at least one water-insoluble polymer comprising ethyl
cellulose and hydroxypropyl methyl cellulose. In addition, the
composition of a particle carrier may occupy about 35-95% by
weight, the composition of a drug layer may occupy about 5-60% by
weight, and the composition of a controlled release layer may
occupy about 0.5-20% by weight, wherein the mixture of (+)
trans-sobrerol and (-) trans-sobrerol may occupy about 40-90% by
weight of the composition of a drug layer.
[0120] In addition, in another embodiment, for the pharmaceutical
formulation for a controlled release dosage form of at least one
compound having Formula (I), Formula (II) or Formula (III), the at
least one compound having Formula (I), Formula (II) or Formula
(III), or its geometric isomer, enantiomer, diastereomer or
pharmaceutically acceptable salt mentioned above may have any one
of Formula (V) to Formula (XVIII) shown above. In one specific
embodiment, for the pharmaceutical formulation for a controlled
release dosage form of at least one compound having Formula (I),
Formula (II) or Formula (III), the at least one compound having
Formula (I), Formula (II) or Formula or its geometric isomer,
enantiomer, diastereomer or pharmaceutically acceptable salt
mentioned above may be at least one compound having Formula (I) and
have any one of Formula (V) to Formula (XVI) shown above. In
another specific embodiment, for the pharmaceutical formulation for
a controlled release dosage form of at least one compound having
Formula (I), Formula (II) or Formula (III), the at least one
compound having Formula (I), Formula (II) or Formula (III), or its
geometric isomer, enantiomer, diastereomer or pharmaceutically
acceptable salt mentioned above may be at least one compound having
Formula (II) and have Formula (XVII) shown above. In yet another
specific embodiment, for the pharmaceutical formulation for a
controlled release dosage form of at least one compound having
Formula (I), Formula (II) or Formula (III), the at least one
compound having Formula (I), Formula (II) or Formula (III), or its
geometric isomer, enantiomer, diastereomer or pharmaceutically
acceptable salt mentioned above may be at least one compound having
Formula (III) and have Formula (XVIII) shown above.
[0121] In one embodiment, the pharmaceutical formulation for a
controlled release dosage form of at least one compound having
Formula (I), Formula (II) or Formula (III) may further comprise a
composition of a coating layer coated on the controlled release
layer. The purpose of the coating layer is to prevent the
controlled release layer from being damaged or eroded and lose its
ability to control release.
[0122] The composition of the coating layer may comprise
hydroxypropyl methyl cellulose, polyethylene glycol, lactose, Talc,
titanium dioxide, etc., or a combination thereof. Alternatively,
the composition of the coating layer also can be a commercial
composition, such as Opadry film coating or Kollicoat film coating,
but it is not limited thereto.
[0123] In the embodiment in which the pharmaceutical formulation
for a controlled release dosage form of at least one compound
having Formula (I), Formula (II) or Formula (III) of the present
disclosure further comprise a composition of a coating layer coated
on the controlled release layer, the composition of a particle
carrier may occupy about 35-98% by weight, the composition of a
drug layer may occupy about 1-64% by weight, the composition of a
controlled release layer may occupy about 1-50% by weight, and the
composition of a coating layer may occupy about 1-35% by weight,
wherein the at least one compound having Formula (I), Formula (II)
or Formula (III), or its geometric isomer, enantiomer, diastereomer
or pharmaceutically acceptable salt may occupy about 1-99% by
weight of the composition of a drug layer.
[0124] Any foregoing pharmaceutical formulation for a controlled
release dosage form of at least one compound having Formula (I),
Formula (II) or Formula (III) is capable of decreasing a dosage
and/or dosing frequency to a subject in need of being administered
at least one compound having Formula (I), Formula (II) or Formula
(III), or its geometric isomer, enantiomer, diastereomer or
pharmaceutically acceptable salt.
[0125] Moreover, the subject in need of being administered at least
one compound having Formula (I), Formula (II) or Formula (III), or
its geometric isomer, enantiomer, diastereomer or pharmaceutically
acceptable salt may comprise a subject suffering from a disease
which can be treated by at least one compound having Formula (I),
Formula (II) or Formula (III), or its geometric isomer, enantiomer,
diastereomer or pharmaceutically acceptable salt, but it is not
limited thereto. In one embodiment, the disease may comprise, but
is not limited to, an autoimmune neurological disease and/or a
neurodegenerative disease. In one specific embodiment, the disease
may be multiple sclerosis.
[0126] The foregoing subject may include, but is not limited to, a
vertebrate. The vertebrate mentioned above may include a fish, an
amphibian, a reptile, a bird, or a mammal, but it is not limited
thereto. Examples of mammals include, but are not limited to, a
human, an orangutan, monkey, a horse, a donkey, a dog, a cat, a
rabbit, a guinea pig, a rat, and a mouse. In one embodiment, the
subject is a human.
EXAMPLES
Example 1
Effects of Sobrerol and Derivatives Thereof on Inhibition of LPS
Induced Inflammation in BV-2 Cells
1. Method
[0127] BV-2 cells (8.times.10.sup.3 cells/mL) were seeded in a
96-well plate cultured under 37.degree. C., 5% CO.sub.2 overnight.
The cells were divided into a naive group (without an.sub.i
treatment), a control group (only treated with LPS) and
experimental groups (treated with LPS and a testing compound).
[0128] The supernatant in the well was removed. After that,
different concentrations of a testing compound was added to the
cells to react with the cells for 1 hour (culture medium was added
to the cells for a control group), and then LPS (100 ng/mL) was
added to the cell.
[0129] After reacting for 24 hours, the supernatant in the plate
was taken and IL-6 expressing amount was detected by Mouse IL-6
ELISA Ready-SET-Go (Invitrogen; Cat. No. 88-7064-88) according to
the manufacturer's recommended procedure.
[0130] Moreover, 50 it of culturing medium containing MTT (0.5
mg/mL) was to the cell part in the plate and cultured under
37.degree. C. and 5% CO.sub.2 for 90 minutes, and then 150 .mu.L,
DMSO was added to the plate and the plate was shaken for 5-10
minutes. Finally, OD.sub.570 was read by a continuous wavelength
microplate analyzer, and cell viability was calculated using the
following formula:
Cell viability (%)=(OD value of the experimental group/OD value of
the control group).times.100.
[0131] CC.sub.50 value for cell viability of a testing compound and
IC value for IL-6 expression of a testing compound were calculated
based on cell viabilities at different concentrations of the
testing compound and IL-6 expression amounts of the cells at
different concentrations of the testing compound, respectively.
2. Results
[0132] The results are shown in Table 1.
TABLE-US-00001 TABLE 1 CC.sub.50 values for cell viability and
IC.sub.50 values for IL-6 expression of sobrerol and derivatives
thereof CC.sub.50 IC.sub.50 for IL-6 for cell Compound Molecular
expression viability Number Formula weight (.mu.M) (.mu.M) SK2 ((-)
trans- sobrerol) ##STR00012## 170.25 182.8 .+-. 21.8 >200
TMUS-0124-4a ##STR00013## 274.36 62.2 >100 Formula (V)
TMUS-0124-4b ##STR00014## 288.39 32.1 >100 Formula (VI)
TMUS-0124-4c ##STR00015## 302.41 38.2 >100 Formula (VII)
TMUS-0124-4d ##STR00016## 319.36 48.1 >100 Formula (VIII)
TMUS-0124-4e ##STR00017## 304.39 50.8 >100 Formula (IX)
TMUS-0124-4f ##STR00018## 268.4 38.0 >100 Formula (X)
TMUS-0503-m1 ##STR00019## 184.28 <10 >100 Formula (XI)
TMUS-0503-b1 ##STR00020## 260.38 <10 >100 Formula (XII)
TMUS-0503-o1 ##STR00021## 168.24 <10 >100 Formula (XIII)
TMUS-0503-c1 ##STR00022## 152.24 30-100 >100 Formula (XVII)
TMUS-0503-c2 ##STR00023## 249.15 30-100 >100 Formula (XVIII)
TMUS-0503-H2 ##STR00024## 113.98 <10 >100 Formula (XIV)
TMUS-0503-H3 ##STR00025## 172.27 30-100 >100 Formula (XV)
TMUS-0503-H4 ##STR00026## 172.27 30-100 >100 Formula (XVI)
[0133] Based on the results shown in above Table 1, it is clear
that the derivatives of sobrerol which are tested are capable of
inhibiting LPS-induced IL-6 expression in BV-2 cells. In other
words, the derivatives of sobrerol which are tested can inhibit
LPS-induced inflammation.
Example 2
Preparation of Liquid Dosage Form of Sobrerol
[0134] 30 mg powder of (-) trans-sobrerol, 60 mg PEO-PPO-PEO
(poly(ethylene oxide).sub.76-polypropylene
oxide).sub.30-poly(ethylene oxide).sub.76; MW 6800) (6%) and 400 mg
powder of 2-hydroxypropyl-beta cyclodextrin (40%) were dissolved in
1 ml deionized water (%: mg/100 .mu.l water)in a microcentrifuge
tube to form a mixture. After that, the microcentrifuge tube was
shaken under room temperature until the mixture therein become
transparent to complete the preparation of a liquid dosage form of
sobrerol.
Example 3
A. Controlled Release Dosage Form of 17% Otrans-Sobrerol
1. Preparation of Controlled Release Dosage Form of 17%
Trans-Sobrerol
[0135] 50 g of (-)trans-sobrerol and 20 g of polyvinylpyrrolidone
were dissolved in 250 g of ethanol to form a first spraying
solution. 200 g of microcrystalline cellulose spheres (particle
size was about 25-35 mesh number, about 500-710 .mu.m) was
introduced into a fluid-bed granulator and spraying-coated with the
spraying solution (spray volume: 0.6-2.0 g/minute; spray air
pressure; 0.4-0.6 kg/cm.sup.2; exhaust air temperature:
20-30.degree. C.; inlet air temperature: 25-40.degree. C.) to
obtain (-)trans-sobrerol drug carrying-panicles (uncoated-drug
carrying particles).
[0136] 18.6 g of ethyl cellulose and 2.1 g of hydroxypropyl methyl
cellulose were dissolved in a mixture solution of 185.6 g of
ethanol and 20.7 g of pure water (with a ratio of about 9:1) and
stirred to be evenly dispersed in the mixture solution to form a
second spraying solution.
[0137] 270 g of (-)trans-sobrerol drug carrying-particles was
introduced into a fluid-bed granulator and spraying-coated with the
second spraying solution (spray volume: 0.2-1.0 g/minute, spray air
pressure: 0.4-0.6 kgs/cm.sup.2; exhaust air temperature:
20-26.degree. C.; inlet air temperature: 23.30.degree. C.) to
obtain controlled release particles with 17% trans-sobrerol
(coated- drug carrying particles).
2. Dissolution Testing for Controlled Release Particles with 17%
Trans-Sobrerol
[0138] Dissolution testing was performed on the uncoated-drug
carrying particles (without controlled release effect) and
coated-drug carrying particles (with controlled release effect)
obtained above to compare the dissolution rates of the two kinds of
particles.
[0139] Basket method was used in the dissolution testing, and the
process of the dissolution testing is described in the
following.
[0140] 1000 ml pure water was added to a testing container, and
then the testing container was configured to a dissolution tester,
and the water temperature was set to 37.degree. C. A testing sample
(191 mg uncoated-drug carrying particles or 200 mg coated-drug
carrying particles) was placed in a basket. When the temperature of
the water in the testing container reached to 37.0.+-.0.5.degree.
C., the basket was descended to the testing container with a
stirring rate of 75 rpm to begin the dissolution (initial point).
Samplings were performed at 5, 15, 30, 60, 120, 180 and 240 minutes
after the initial point, respectively, and sampling volume was 10
ml. The samples were filtered by a 0.45 .mu.m filter and then
component contents thereof were analyzed by high performance liquid
chromatography (HPLC), respectively.
[0141] The results of the dissolution testing for controlled
release particles with 17% trans-sobrerol (coated-drug carrying
particles) and trans-sobrerol drug carrying-particles (uncoated-
drug carrying particles) are shown in FIG. 1.
[0142] The results show that 15 minutes after the beginning of the
dissolution testing in which pure water was used as the solvent,
the dissolution rate of the trans-sobrerol drug carrying-particles
(uncoated-drug carrying particles) was 100% while the dissolution
rate of the controlled release particles with 17% trans-sobrerol
(coated-drug carrying particles) was less than 20%. 120 minutes
after the beginning of the dissolution testing, the dissolution
rate of the controlled release particles with 17% trans-sobrerol
(coated-drug carrying particles) was about 80%. According to the
results mentioned above, it is confirmed that the controlled
release layer has controlled release effect on the dissolution rate
of trans-sobrerol.
B. Controlled Release Dosage Form of 20% (+)(-)Trans-Sobrerol
1. Preparation of Controlled Release Dosage Form of 20%
(+)-Trans-Sobrerol
[0143] 60 g of (+)(-)trans-sobrerol and 24 g of
polyvinylpyrrolidone were dissolved in 300 g of ethanol to form a
first spraying solution. 200 g of microcrystalline cellulose
spheres (particle size was about 25-35 mesh number, about 500-710
.mu.m) was introduced into a fluid-bed granulator and
spraying-coated with the spraying solution (spray volume: 0.6-2.0
g/minute; spray air pressure: 0.4-0.6 kg/cm.sup.2 exhaust air
temperature: 20-30.degree. C.; inlet air temperature: 25-40.degree.
C.) to obtain (.+-.)(-) trans-sobrerol drug carrying-particles
(uncoated-drug carrying particles).
[0144] 20.3 g of ethyl cellulose and 2.3 g of hydroxypropyl methyl
cellulose were dissolved in a mixture solution of 202.5 g of
ethanol and 22.5 g of pure water (with a weight ratio of about 9:1)
and stirred to be evenly dispersed in the mixture solution to for a
second spraying solution.
[0145] 284 g of (+)(-)trans-sobrerol drug carrying-particles was
introduced into a fluid-bed granulator and spraying-coated with the
second spraying solution (spray volume: 0.2-1.0 g/minute; spray air
pressure: 0.4-0.6 kg/cm.sup.2; exhaust air temperature:
20-35.degree. C., inlet air temperature: 25-40.degree. C.) to
obtain controlled release particles with 20% (+)(-)trans-sobrerol
(coated-drug carrying particles). The controlled release particles
with 20% (+)(-)trans-sobrerol (coated-drug carrying particles) were
made in two batches.
2. Dissolution Testing for Controlled Release Particles with 20%
Sobrerol
[0146] Dissolution testing was performed on the uncoated-drug
carrying particles (without controlled release effect) and
coated-drug carrying particles (with controlled release effect)
obtained above to compare the dissolution rates of the two kinds of
particles.
[0147] Basket method was used in the dissolution testing, and the
process of the dissolution testing is described in the
following.
[0148] 1000 ml pure water was added to a testing container, and
then the testing container was configured to a dissolution tester,
and the water temperature was set to 37.degree. C. A testing sample
(193 mg uncoated-drug carrying particles or 208 mg coated-drug
carrying particles) was placed in a basket. When the temperature of
the water in the testing container reached to 37.0.+-.0.5.degree.
C., the basket was descended to the testing container with a
stirring rate of 75 rpm to begin the dissolution (initial point).
Samplings were performed at 5, 15, 30, 60, 120, 180 and 240 minutes
after the initial point, respectively, and sampling volume was 10
ml. The samples were filtered by a 0.45 .mu.m filter and then
component contents thereof were analyzed by high performance liquid
chromatography (HPLC), respectively.
[0149] The results of the dissolution testing for controlled
release particles with 20% sobrerol (coated-drug carrying
particles) and sobrerol drug carrying-particles (uncoated-drug
carrying particles) are shown in FIG. 2.
[0150] The results show that 30 minutes after the beginning of the
dissolution testing in which pure water was used as the solvent,
the dissolution rate of the sobrerol drug carrying-particles
(uncoated-drug carrying particles) was 100% while the dissolution
rates of the two batches of controlled release particles with 20%
sobrerol (coated-drug carrying particles) both were less than 40%.
120 minutes after the beginning of the dissolution testing, the
dissolution rates of the two hatches of controlled release
particles with 20% sobrerol (coated-drug carrying particles) both
were about 80%. According to the results mentioned above, it is
confirmed that the controlled release layer has controlled release
effect on the dissolution rate of sobrerol.
C. Controlled Release Dosage Form of 8% (+)(-)Trans-Sobrerol
[0151] 1. Preparation of Controlled Release Dosage Form of 8%
(+)(-)Trans-Sobrerol
[0152] 2.0 g of (+)(-)trans-sobrerol and 8 g of
polyvinylpyrrolidone were dissolved in 100 g of ethanol to form a
first spraying solution. 200 g of microcrystalline cellulose
spheres (particle size was about 25-35 mesh number, about 500-710
.mu.m) was introduced into a fluid-bed granulator and
spraying-coated with the spraying solution (spray volume: 0.6-1.4
g/minute; spray air pressure: 0.4-0.6 kg/cm.sup.2 exhaust air
temperature: 20-26.degree. C.; inlet air temperature: 22-32.degree.
C.) to obtain (.+-.)(-) trans-sobrerol drug carrying-particles
(uncoated-drug carrying particles).
[0153] 18.56 g of ethyl cellulose and 2.07 .sub.g of hydroxypropyl
methyl cellulose were dissolved in a mixture solution of 185.6 g of
ethanol and 20.7 g of pure water (with a weight ratio of about 9:1)
and stirred to be evenly dispersed in the mixture solution to form
a second spraying solution.
[0154] 228 g of (+)(-)trans-sobrerol drug carrying-particles was
introduced into a fluid-bed granulator and spraying-coated with the
second spraying solution (spray volume: 0.4-1.2 g/minute; spray air
pressure: 0.4-0.6 kg/cm.sup.2; exhaust air temperature:
20.26.degree. C.; inlet air temperature: 23-30.degree. C.) to
obtain controlled release particles with 8% (+)(-)trans-sobrerol
(coated-drug carrying particles).
2. Dissolution Testing for Controlled Release Particles with 8%
Sobrerol
[0155] Dissolution testing was performed on the uncoated-drug
carrying particles (without controlled release effect) and
coated-drug carrying particles (with controlled release effect)
obtained above to compare the dissolution rates of the two kinds of
particles.
[0156] Basket method was used in the dissolution testing, and the
process of the dissolution testing is described in the
following.
[0157] 1000 ml pure water was added to a testing container, and
then the testing container was configured to a dissolution tester,
and the water temperature was set to 37.degree. C. A testing sample
(190 mg uncoated-drug carrying particles or 204 mg coated-drug
carrying particles) was placed in a basket. When the temperature of
the water in the testing container reached to 37.0.+-.0.5.degree.
C., the basket was descended to the testing container with a
stirring rate of 75 rpm to begin the dissolution (initial point).
Samplings were performed at 5, 15, 30, 60, 120, 180 and 240 minutes
after the initial point, respectively, and sampling volume was 10
ml, The samples were filtered by a 0.45 .mu.m filter and then
component contents thereof were analyzed by high performance liquid
chromatography (HPLC), respectively.
[0158] The results of the dissolution testing for controlled
release particles with 8% sobrerol (coated-drug carrying particles)
and sobrerol drug carrying-particles (uncoated-drug carrying
particles) are shown in FIG. 3.
[0159] The results show that 15 minutes after the beginning of the
dissolution testing in which pure water was used as the solvent,
the dissolution rate of the sobrerol drug carrying-particles
(uncoated-drug carrying particles) was 100% while the dissolution
rate of the controlled release particles with 8% sobrerol
(coated-drug carrying particles) was less than 20%. 180 minutes
after the beginning of the dissolution testing, the dissolution
rate of the controlled release particles with 8% sobrerol
(coated-drug carrying particles) was about 80%. According to the
results mentioned above, it is confirmed that the controlled
release layer has controlled release effect on the dissolution rate
of sobrerol.
D. Controlled Release Dosage Form of 32% (+)(-)Trans-Sobrerol
1. Preparation of Controlled Release Dosage Form of 32%
(+)(-)Trans-Sobrerol
[0160] 125 g of (+)(-)trans-sobrerol and 50 g of
polyvinylpyrrolidone were dissolved in 625 g of ethanol to form a
first spraying solution. 200 g of microcrystalline cellulose
spheres (particle size was about 25-35 mesh number, about 500-710
.mu.m) was introduced into a fluid-bed granulator and
spraying-coated with the spraying solution (spray volume: 0.6-2.8
g/minute; spray air pressure: 0.4-0.75 kg/cm.sup.2; exhaust air
temperature: 20-26.degree. C.; inlet air temperature: 24-31.degree.
C.) to obtain (+)(-) trans-sobrerol drug carrying-particles
(uncoated-drug carrying particles).
[0161] 18.56 g of ethyl cellulose and 2.07 g of hydroxypropyl
methyl cellulose were dissolved in a mixture solution of 185.6 g of
ethanol and 20.7 g of pure water (with a weight ratio of about 9:1)
and stirred to be evenly dispersed in the mixture solution to form
a second spraying solution.
[0162] 375 g of (+)(-)trans-sobrerol drug carrying-particles was
introduced into a fluid-bed granulator and spraying-coated with the
second spraying solution (spray volume: 0.8-1.2 g/minute; spray air
pressure: 0.8-0.9 kg/cm.sup.2; exhaust air temperature:
20-24.degree. C., inlet air temperature: 22-29.degree. C.) to
obtain controlled release particles with 32% (+)(-)trans-sobrerol
(coated-drug carrying particles).
2. Dissolution Testing for Controlled Release Particles with 32%
Sobrerol
[0163] Dissolution testing was performed on the uncoated-drug
carrying particles (without controlled release effect) and
coated-drug carrying particles (with controlled release effect)
obtained above to compare the dissolution rates of the two kinds of
particles.
[0164] Basket method was used in the dissolution testing, and the
process of the dissolution testing is described in the
following.
[0165] 1000 ml pure water was added to a testing container, and
then the testing container was configured to a dissolution tester,
and the water temperature was set to 37.degree. C., A testing
sample (190 mg uncoated-drug carrying particles or 198 mg
coated-drug carrying particles) was placed in a basket. When the
temperature of the water in the testing container reached to
37.0+0.5.degree. C., the basket was descended to the testing
container with a stirring rate of 75 rpm to begin the dissolution
(initial point) Samplings were performed at 5, 15, 30, 60, 120, 180
and 240 minutes after the initial point, respectively, and sampling
volume was 10 ml. The samples were filtered by a 0.45 .mu.m filter
and then component contents thereof were analyzed by high
performance liquid chromatography (HPLC), respectively.
[0166] The results of the dissolution testing for controlled
release particles with 32% sobrerol (coated-drug carrying
particles) and sobrerol drug carrying-particles (uncoated-drug
carrying particles) are shown in FIG. 4.
[0167] The results show that 15 minutes after the beginning of the
dissolution testing in which pure water was used as the solvent,
the dissolution rate of the sobrerol drug carrying-particles
(uncoated-drug carrying particles) was 100% while the dissolution
rate of the controlled release particles with 32% sobrerol
(coated-drug carrying particles) was less than 5%. 240 minutes
after the beginning of the dissolution testing, the dissolution
rate of the controlled release particles with 32% sobrerol
(coated-drug carrying particles) was about 57%. According to the
results mentioned above, it is confirmed that the controlled
release layer has controlled release effect on the dissolution rate
of sobrerol.
Example 4
[0168] MOG induced IFN-.gamma. secretion and IL-2 secretion in
splenocyte isolated from mice of experimental autoimmune
encephalomyelitis (EAE) model
[0169] EAE was induced in C57B116 mice. The mice were immunized on
Day 0 by subcutaneous injection with 200 .mu.g of myelin
oligodendrocyte glycoprotein (MOG) in incomplete Freund's adjuvant
(IFA) containing 400 .mu.g of heat-killed Mycobaterium tuberculosis
H37Ra. Pertussis toxin (500 ng) was intraperitoneally injected on
Day 0 and Day 2 after the mice were immunized with the emulsion.
The mice were sacrifice on Day 30 post-immunization. Spleens of the
mice were harvest and then splenocytes were isolated and cultured
in presence or absence of the 20 .mu.g/ml MOG peptide in 10% FBS
RPMI1640 medium. Testing compound was added to the culture and
maintained at 37.degree. C. 5% CO.sub.2 for 48 hours. The
concentrations of IFN-.gamma. and IL-2 in the supernatant of the
culture were determined by ELISA according to the manufacturer's
instructions.
2. Results
[0170] The results are shown in Table 2.
TABLE-US-00002 TABLE 2 IFN-.gamma. inhibition and IL-2 inhibition
of sobrerol and derivatives thereof IFN- IL-2 Compound Molecular
Concentration .gamma.inhibition inhibition Number Formula weight
.mu.M % % SK0((+)(-) trans- Sobrerol) ##STR00027## 170.75 300 10 16
Formula (IV) SK1 ((+) trans- Sobrerol) ##STR00028## 170.25 200 24 0
SK2 ((-) trans- sobrerol) ##STR00029## 170.25 200 34 0 TMUS-0124-4a
##STR00030## 274.36 200 77 31 Formula (V) TMUS-0124-4b ##STR00031##
288.39 100 88 48 Formula (VI) TMUS-0124-4c ##STR00032## 302.41 200
78 23 Formula (VII) TMUS-0124-4d ##STR00033## 319.36 200 79 22
Formula (VIII) TMUS-0124-4e ##STR00034## 304.39 100 86 59 Formula
(IX) TMUS-0124-4f ##STR00035## 268.4 200 59 8 Formula (X)
TMUS-0503-m1 ##STR00036## 184.28 100 17 21 Formula (XI)
TMUS-0503-b1 ##STR00037## 260.38 300 20 15 Formula (XII)
TMUS-0503-o1 ##STR00038## 168.24 200 56 40 Formula (XIII)
TMUS-0503-c1 ##STR00039## 152.24 300 23 22 Formula (XVII)
TMUS-0503-c2 ##STR00040## 249.15 100 31 13 Formula (XVIII)
TMUS-0503-H2 ##STR00041## 113.98 100 33 16 Formula (XIV)
TMUS-0503-H4 ##STR00042## 172.27 300 42 19 Formula (XVI)
Example 5
Animal Experiment
A. Material
[0171] a. Animals
[0172] The female C57BL/6 mice, aged 8 weeks old, purchased from
the National Laboratory Animal Center (NLAC. Taiwan) were used in
this study. The animals of C57BL/6 mice had been widely used with
abundant references and data, and fit to the evaluation of the
Experimental autoimmune encephalomyelitis (EAE) model. The mice
were housed with free access to water and food under a constant
environment that maintained at 23.+-.2.degree. C., relative
humidity 40-70% and on a 12:12-hour light-dark cycle at the animal
research facility of the industrial Technology Research institute
(ITRI, Taiwan).
[0173] In order to ensure the health of the animals, clinical
observation and record were performed by veterinarians and
investigators of ITRI during the period of quarantine and
experiment daily, respectively. The animal use protocol listed
below has been reviewed and approved by the Institutional Animal
Care and Use Committee (IACUC) of ITRI.
b. Reagents
[0174] Incomplete Freund's adjuvant (WA) (Sigma-Aldrich, USA);
Myelin Oligodendrocyte glycoprotein (MOG.sub.35-55) peptide
(Kelowna International Scientific company, Taiwan); Pertussis Toxin
(List Biological Laboratories, USA); Mycobacterium Tuberculosis
H37RA (Difco Laboratories, Germany); A mixture of (+)
trans-sobrerol and (-) trans-sobrerol (Mucoflux capsules); (-)
trans-sobrerol (Sigma-Aldrich)
B. Methods
3. Therapeutic Administration Experiment
3-1 Testing Drug Administration After Experimental Autoimmune
Encephalomyelitis (EAE) Induction and Clinical Assessment
[0175] For induction of EAE, female C57BL/6 mice were
subcutaneously injected with 200 .mu.l emulsion including 200 .mu.g
MOG.sub.35-55 peptide and 400 .mu.g Mycobacterium tuberculosis
H37Ra, then intraperitoneally injected with 500 ng pertussis toxin,
and after 48 hours, the mice were subjected another intraperitoneal
injection with 500 ng pertussis toxin.
[0176] From Day 7 post to the induction, the EAE clinical symptoms
of the mice were recorded daily according to the recognized Ataxia
score (grading of nervous system disorder) and EAE score as the
scoring criteria (description of Ataxia score and EAE score are as
follows). When the mice began to appear Ataxia score 0.sup.++ the
mice were grouped by S-type grouping method and administration of
testing drug (a mixture of (+) trans-sobrerol and (-)
trans-sobrerol (Mucoflux capsules), (-) trans-sobrerol
(Sigma-Aldrich) or a liquid dosage form of (-) trans-sobrerol
prepared in Example 2 mentioned above) was begun and continued for
14 days. On Day 15 of the administration of testing drug, the mice
were sacrificed, and blood or related organs thereof were collected
for subsequent analysis.
[0177] The criteria of Ataxia score that modified from Metten et al
(2004) are shown as follows: 0.sup.+: The rear foot of the animal
is splayed while moving, swing left and right, and gait imbalance;
0.sup.++: When grasping the rear neck of the animal to observe
whether its tail can be raised by itself and to test the tensile
strength of its tail by fingers, the tail appears unable to be
raised by itself as well as reduced tension.
[0178] The criteria of EAE score are shown as follows: Score 0: no
EAE symptoms; Score 0.5: Temporal weak tail, sometimes raised;
Score 1: Limp tail, unable to lift normally; Score 2: Paralyzed
tail or slightly hind limb weakness; Score 3: Moderate to severe
hind limb paralysis or mild forelimb weakness; Score 4: Complete
hind limb paralysis or moderate to severe forelimb weakness; Score
5: Limb paralysis accompanied by incontinence or presenting a dying
state; Score 6: Death.
3-2. Histology and Immunohistochemistry
[0179] The mice were euthanized at day 15 post to onset of EAE.
Spinal cord was removed and fixed in 10% phosphate-buffered
formaldehyde. Paraffin-embedded 3 .mu.m-thick cross sections of
spinal cord were stained with hematoxylin and eosin in order to
confirm tissue lesion. Another slides were stained with Luxol fast
blue for examination of demyelination. Lesions were evaluated based
on demyelination, inflammation, axonal swelling and gliosis which
are scored based on the criteria shown in Table 2:
TABLE-US-00003 TABLE 2 Lesion Score Description Demyelination 0 No
demyelination 1 Few, scattered demyelination 2 Small groups of
demyelination 3 Large groups of demyelination 4 Massive
demyelination over one half of the white matter 5 Widespread
demyelination Inflammatory 0 No inflammatory cells 1 Few, scattered
inflammatory cells 2 Inflammatory cells infiltrate into
perivascular cuffs 3 Perivascular cuffing with extension into
parenchyma 4 Extensive perivascular cuffing with increasing
subarachnoid and parenchymal inflammation Axonal swelling 0 No
axonal swelling 1 Few, scattered swollen axons 2 Small groups of
swollen axons 3 Large groups of swollen axons Gliosis 0 No gliosis
1 Minimal (1-10%) 2 Slight (11-25%) 3 Moderate (26-50%) 4
Moderately severe (51-75%) 5 Severe/high (76-100%)
4. Prophylaxis Administration Experiment
[0180] Testing drug administration after experimental autoimmune
encephalomyelitis (EAE) induction and before experimental
autoimmune encephalomyelitis (EAE) signs onset and clinical
assessment
[0181] For induction of EAE, female C57BL/6 mice were
subcutaneously injected with 200 .mu.l A emulsion including 200
.mu.g MOG.sub.35-55 peptide and 400 .mu.g Mycobacterium
tuberculosis H37Ra, then intraperitoneal injected with 500 ng
pertussis toxin, and after 48 hours, the mice were subjected
another intraperitoneal injection with 500 ng pertussis toxin.
[0182] From Day 7 post to the induction, the mice were grouped
according the weight by S-type grouping method and administration
of testing drug ((-) trans-sobrerol (Sigma-Aldrich) was begun and
continued for 14 days. On Day 21 after MOG.sub.35-55 immunization,
the mice were sacrificed, and blood or related organs thereof were
collected for subsequent analysis. The EAE clinical symptoms of the
mice were recorded daily according to the EAE score as the scoring
criteria (description of Ataxia score and EAE score are as
follows).
[0183] The criteria of EAE score are shown as follows: Score 0: no
EAE symptoms; Score 0.5: Temporal weak tail, sometimes raised;
Score 1: Limp tail, unable to lift normally; Score 2: Paralyzed
tail or slightly hind limb weakness; Score 3: Moderate to severe
hind limb paralysis or mild forelimb weakness; Score 4: Complete
hind limb paralysis or moderate to severe forelimb weakness; Score
5: Limb paralysis accompanied by incontinence or presenting a dying
state; Score 6: Death.
C. Results
1. Therapeutic Administration Experiment
1-1. Administration of (-) Trans-Sobrerol After Experimental
Autoimmune Encephalomyelitis (EAE) Induction
[0184] (-) trans-sobrerol was dissolved in vehicle
(DMSO:CrEL:saline 10:10:80) to form a solution of (-)
trans-sobrerol.
[0185] Based on method described in the section "3-1 Testing drug
administration after experimental autoimmune encephalomyelitis
(EAE) induction and clinical assessment" of "3. Therapeutic
administration" of above "B. Methods", different doses of (-)
trans-sobrerol and vehicle (DMSO:CrEL:saline=10:10:80) were
administered to the EAE induced mice by different dosing
frequencies and then EAE scores of the mice were evaluated.
[0186] The results are shown in FIGS. 5A, 5B, and 5C. FIG. 5A shows
respective EAE scores of the mice administered with 30 mg/kg and
100 mg/kg dosages of (-) trans-sobrerol and the mice administered
with vehicle (DMSO:CrEL:saline=10:10:80), one time a day. FIG. 5B
shows respective EAE scores of the mice administered with 50 mg/kg
and 100 mg/kg dosages of (-) trans-sobrerol, and the mice
administered with vehicle (DMSO:CrEL:saline=1.0:10:80), two times a
day. FIG. 5C shows respective EAE scores of the mice administered
with 10 mg/kg, 25 mg/kg, 50 mg/kg and 100 mg/kg dosages of (-)
trans-sobrerol, the mice administered with vehicle
(DMSO:CrEL:saline=10:10:80), three times a day, and the mice
administered with 100 mg/kg dosage of dimethyl fumarate two times a
day.
[0187] According to the results shown in FIGS. 5A, 5B and 5C, it is
clear that (-) trans-sobrerol can significantly alleviating
symptoms of EAE in the EAE induced mice.
[0188] Lesions of spinal cords of the mice were evaluated based on
demyelination, inflammation, axonal swelling and gliosis based on
the method described in the section "3-2. Histology and
immunohistochemistry" of "3. Therapeutic administration" of above
"B. Methods".
[0189] The results are shown in FIGS. 6A-6D and FIGS. 7A-7D.
[0190] In FIG. 6A shows the result of hematoxylin and eosin stain
for the spinal cords of the mice treated with 100 mg/kg dosages of
(-) trans-sobrerol three times a day, FIG. 6B shows the results of
hematoxylin and eosin stain for the spinal cords of the mice
treated with vehicle three times a day, FIG. 6C shows the result of
Luxol fast blue stain for the spinal cords of the mice treated with
treated with 100 mg/kg dosages of (-) trans-sobrerol three times a
day, and FIG. 6D shows the results of Luxol fast blue stain for the
spinal cords of the mice treated with vehicle three times a
day.
[0191] FIG. 7A shows demyelination scores of spinal cords of the
mice with 100 mg/kg dosages of (-) trans-sobrerol three times a
day, the mice treated with vehicle three times a day, and the mice
without any treatment. FIG. 7B shows axonal swelling scores of
spinal cords of the mice with 100 mg/kg dosages of (-)
trans-sobrerol three times a day, the mice treated with vehicle
three times a day, and the mice without any treatment. FIG. 7C
shows inflammation scores of spinal cords of the mice with 100
mg/kg dosages of (-) trans-sobrerol three times a day, the mice
treated with vehicle three times a day, and the mice without any
treatment. FIG. 7D shows gliosis scores of spinal cords of the mice
with 100 mg/kg dosages of (-) trans-sobrerol three times a day, the
mice treated with vehicle three times a day, and the mice without
any treatment.
[0192] Based on the results shown in FIGS. 6A-6D and FIGS. 7A-7D,
it is clear that sobrerol is capable of effectively alleviating
demyelination, inflammation, axonal swelling and gliosis in spinal
cords of the EAE induced mice.
1-2. Administration of Mixture of (+) Trans-Sobrerol and (-)
Trans-Sobrerol After Experimental Autoimmune Encephalomyelitis
(EAE) Induction
[0193] Mucoflux capsules containing a mixture of (+) trans-sobrerol
and (-) trans-sobrerol were shucked and the powder in the capsules
was dissolved in vehicle(DMSO:CrEL:saline=10:10:80)to form a
solution of a mixture of (+) trans-sobrerol and (-)
trans-sobrerol.
[0194] Based on method described in the section "3-1 Testing drug
administration after experimental autoimmune encephalomyelitis
(EAE) induction and clinical assessment" of "3. Therapeutic
administration" of above "B. Methods", different doses of the
mixture of (+) trans-sobrerol and (-) trans-sobrerol and vehicle
(DMSO:CrEL:saline=10:10:80) were administered to the EAE induced
mice by different dosing frequencies and then EAE scores of the
mice were evaluated.
[0195] The results are shown in FIG. 8A and 8B. FIG. 8A shows
respective EAE scores of the mice administered with 100 mg/kg
dosage of the mixture of (+) trans-sobrerol and (-) trans-sobrerol
and the mice administered with vehicle (DMSO:CrEL:saline-10:10:80),
one time a day. FIG. 8B shows respective EAE scores of the mice
administered with 15 mg/kg, 50 mg/kg and 100 mg/kg dosages of the
mixture of (+) trans-sobrerol and (-) trans-sobrerol and the mice
administered with vehicle (DMSO:CrEL:saline=10:10:80), two times a
day.
[0196] According to the results shown in FIGS. 8A and 8B, it is
clear that mixture of (-) trans-sobrerol and (-) trans-sobrerol can
significantly alleviating symptoms of EAE in the EAE induced
mice.
1-3. Administration of a Liquid Dosage Form of (-) Trans-Sobrerol
After Experimental Autoimmune Encephalomyelitis (EAE) Induction
[0197] Based on method described in the section "3-1 Testing drug
administration after experimental autoimmune encephalomyelitis
(EAE) induction and clinical assessment" of "3. Therapeutic
administration" of above "B. Methods", different doses of the
liquid dosage form of (-) trans-sobrerol prepared, (-)
trans-sobrerol and vehicle (6% PEO-PPO-PEO and 40%
2-hydroxypropyl-beta cyclodextrin in water (%: mg/100 .mu.l water))
were administered to the EAE induced mice by different dosing
frequencies and then EAE scores of the mice were evaluated.
[0198] The results are shown in FIGS. 9A and 9B. FIG. 9A shows
respective EAE scores of the mice administered with 150 mg/kg
dosage of the liquid dosage form of (-) trans-sobrerol prepared two
times a day and 300 mg/kg dosage of the liquid dosage form of (-)
trans-sobrerol prepared one time a day, the mice administered with
100 mg/kg dosage of (-) trans-sobrerol three times a day, and the
mice administered with vehicle (6% PEO-PPO-PEO and 40%
2-hydroxypropyl-beta cyclodextrin (%: mg/100 .mu.l water)) two
times a day and vehicle (DMSO:CrEL:saline=10:10:80) three times a
day. FIG. 9B shows respective EAE scores at Day 15 after EAE sings
onset of the mice administered with 150 mg/kg dosage of the liquid
dosage form of (-) trans-sobrerol prepared two times a day and 300
mg/kg dosage of the liquid dosage form of (-) trans-sobrerol
prepared one time a day, the mice administered with 100 mg/kg
dosage of (-) trans-sobrerol three times a day, and the mice
administered with vehicle (6% PEO-PPO-PEO and 40%
2-hydroxypropyl-beta cyclodextrin (%: mg/100 .mu.l water)) two
times a day and vehicle (DMSO:CrEL:saline=10:10:80) three times a
day.
[0199] Based on the results shown in FIGS. 9A and 9B, it is clear
that the effects of administration of the liquid dosage form of (-)
trans-sobrerol prepared (300 mg/kg) by one time a day and (-)
trans-sobrerol prepared (150 mg/kg) by two times a day are
equivalent to that of administration of (-) trans-sobrerol (100
mg/kg) by three times a day. In other words, FIGS. 9A and 9B clear
show that the liquid dosage form can reduce the dosing frequencies
required by (-) trans-sobrerol.
2. Prophylaxis Administration Experiment
2-1. Administration of (-) Trans-Sobrerol Before Experimental
Autoimmune Encephalomyelitis (EAE) Signs Onset
[0200] (-) Trans-sobrerol was dissolved in vehicle
(DMSO:CrEL:saline=10:10:80) to form a solution of (-)
trans-sobrerol.
[0201] Based on method described in the section "4. Prophylaxis
administration experiment" of above "B. Methods", administration of
different doses of (-) trans-sobrerol and vehicle
(DMSO:UHL:saline=10:10:80) to the mice were started at day 7 after
the experimental autoimmune encephalomyelitis (EAE) induction by
different dosing frequencies and then EAE scores of the mice were
evaluated.
[0202] The results are shown in FIG. 10. FIG. 10 shows respective
EAE scores of the mice administered with 100 mg/kg dosages of (-)
trans-sobrerol, the mice administered with vehicle
(DMSO:CrEL:saline-10:10:80), and mice administered with 50 mg/kg
dosages of dimethyl fumarate, one time a day.
[0203] According to the results shown in FIG. 10, it is clear that
(-) trans-sobrerol can significantly alleviating symptoms of EAE in
the EAE induced mice.
[0204] It will be apparent to those skilled in the art that various
modifications and variations can be made to the disclosed
embodiments. It is intended that the specification and examples be
considered as exemplary only, with the true scope of the disclosure
being indicated by the following claims and their equivalents.
* * * * *