Broad-spectrum antiviral composition with excellent preservation stabilty

17 Pages·2015·1.17 MB·English

US008545898B2
(12) United States Patent (10) Patent N0.: US 8,545,898 B2
Fukuda et a]. (45) Date of Patent: Oct. 1, 2013
(54) BROAD-SPECTRUM ANTIVIRAL (56) References Cited
COMPOSITION WITH EXCELLENT
PRESERVATION STABILTY U.S. PATENT DOCUMENTS
3,950,500 A * 4/1976 Jaszka ......................... .. 423/480
(75) Inventors: Toshiaki Fukuda, Suita (JP); Koji Abe, 6,200,557 B1 3/2001 Ratcliff
2004/0104127 A1 6/2004 Rojas
Suita (JP); Takashi Shibata, Suita (JP)
FOREIGN PATENT DOCUMENTS
(73) Assignee: Taiko Pharmaceutical Co., Ltd., Osaka
JP 61-181532 A 8/1986
(JP)
JP 11228316 A * 8/1999
JP 11-278808 A 10/1999
( * ) Notice: Subject to any disclaimer, the term of this JP 11-278808 * 12/1999
patent is extended or adjusted under 35 JP 3110724 B2 11/2000
JP 1999-278808 A 4/2001
U.S.C. 154(b) by 289 days.
OTHER PUBLICATIONS
(21) App1.No.: 12/527,338
Puro gene Sales sheet, Downloaded from the internet on Oct. 20, 201 1
from the URL: http://www.bi0-cide.com/up10ads/
(22) PCT Filed: Feb. 15, 2008
Purogene%20Sales%20Sheet.pdf.*
Purogene MSDS, Downloaded from the internet on Oct. 20, 2011
(86) PCT No.: PCT/JP2008/052493
from the URL: http://www.aerosafe.com/media/Purogene.PDF.*
§ 371 (0X1)’ International Search Report of Application PCT/JP2008/052493
dated May 13, 2008.
(2), (4) Date: Sep. 30, 2009
Written Opinion of the International Searching Authority of Appli
cation PCT/JP2008/052493 dated May 13, 2008.
(87) PCT Pub. No.: WO2008/099911
International Preliminary Report on Patentability dated Aug. 19,
PCT Pub. Date: Aug. 21, 2008 2009.
Jun Wen Li et al., “Mechanisms of Inactivation of Hepatitis AVirus
(65) Prior Publication Data in Water by Chlorine Dioxide”, Water Research, v01. 3 8, 2004 (month
unknown), pp. 1514-1519, Elsevier.
US 2010/0028456 A1 Feb. 4, 2010
(Continued)
(30) Foreign Application Priority Data
Primary Examiner * James H Alstrum Acevedo
Feb. 16, 2007 (JP) ............................... .. 2007-036469 Assistant Examiner * Daniel L Branson
(74) Attorney, Agent, or Firm * Osha Liang LLP
(51) Int. Cl.
A01N 59/08 (2006.01) (57) ABSTRACT
A61K 33/14 (2006.01) A composition for a broad-spectrum antiviral agent with
(52) US. Cl. excellent preservation stability, which comprises a pure chlo
USPC ......................................... .. 424/661; 424/600 rine dioxide solution comprising a chlorine dioxide gas dis
(58) Field of Classi?cation Search solved therein, a chlorite, and a pH adjuster.
None
See application ?le for complete search history. 5 Claims, 7 Drawing Sheets
Rotavirus—inactivation effect _
1 2 O (ippm: concentration before 8—month preservation and at preparation)
1 O 0
g
= 8 O
{D
o
E
1:; 6 0 Agent B (containing organic acid)
g T G 6
“5
2 4 O
.H
N
n:
2 0
Agent A (containing inorganic acid salt)
0 l '_i
O 5 O 1 O O 1 5 O 2 O O
Sensitized time (second)
US 8,545,898 B2
Page 2
(56) References Cited Chen, Y.S., et al., “Applied and Environmental Microbiology”, 1990,
vol. 56, No. 5; pp. 1363-1366. (Previously cited in the International
OTHER PUBLICATIONS Search Report dated May 13, 2008, and ?led in the IDS ?led Sep. 30,
2009, with the USPTO).
Yu-Shiaw Chen et al., “Inactivation of Human and Simian Dioxide”, Li, J.W., et al., “Water Research”, 2004, vol. 38; pp. 1614-1519.
Applied and Environmental Microbiology, May 1990, pp. 1363 (Previously cited in the International Search Report dated May 13,
1366, vol. 56, No. 5, American Society for Microbiology. 2008, and ?led in the IDS ?led Sep. 30, 2009, With the USPTO).
Notice of Reasons for Refusal (Of?ce Action) issued Jun. 9, 2010, Handbook of Japanese Pharmaceutical Excipients, Yakuji Nippo
issued by the Japan Patent Of?ce in related Japan Patent Application Ltd., 1994, the lst Edition; pp. 150, 151, 246, 247, and 355. (Previ
No. JP-2008-558l42, With English translation (6 pages). ously cited in the International Search Report dated May 13, 2008,
Patent Disclosure No. l999-278808, Patent Gazette (Previously cited and ?led in the IDS ?led Sep. 30, 2009, With the USPTO).
in the International Search Report dated May 13, 2008, and ?led in
the IDS ?led Sep. 30, 2009, With the USPTO). * cited by examiner
US. Patent 0a. 1, 2013 Sheet 1 017 US 8,545,898 B2
Fig.1
Influenza virus—inactivation effect
(1 ppm: concentration before 8—month preservation and
5. 00 immediately after preparation)
A/New Caledonia (HlNl)
o 4. 50 X
H \ Agent D (stabilized chlorine dioxide)
w k -A - - - *- _ _ .. -A
O _ ,- I - -
-—* 4. 00
0
LO
Q 3. 50
9 Agent 0 (Na hypochlorite)
Fl 3. -_ _ I. _ _ _
_ _ _ _ i
2. 5O
2_ 00 Agent B (containing organic acid)
1. 50
Agent A (containing inorganic acid salt)
1. 00
0.50 ‘Q Q Q Q
O 50 100 150 200
Sensitized time (second)
US. Patent 0a. 1, 2013 Sheet 2 0f7 US 8,545,898 B2
Fig.2
Norovirus (feline calicivirus)—inactivation effect
(10 ppm: concentration before 8—month preservation and
7.00 immediately after preparation)
x! I ' _ _ _
6. 00 Agent E (powdone—lodlne)
Q
0 5. 00
1—4
A
O 4. 00 O G v Q
LO
Q Agent B (containing organic acid)
0 3. 00
[-‘i
2. 00
Agent A (containing inorganic acid salt)
1. ()0
O
i I I | | I
O 3 O 6 O 9 O l 2 O 1 5 O 1 8 O
Sensitized time (second)
US. Patent 0a. 1, 2013 Sheet 3 0f7 US 8,545,898 B2
Fig.3
(a )
Coxsackievirus BS—inactivation effect (sensitized time: 1 minute)
6. 00
5.50 -----A:-------A
’5 Agent D
H 5.00 (stabilized chlorine dioxide)
cow 4' 50 Agent B
v—( 4.00 (containing
v organic acid)
0 3.50
LO
Q 3.00
6 2- 50 Agent A (containing inorganic acid salt)
H 2.00
1. 50
1' 00 l l l l
Oppm 0.1ppm lppm lOppm lOOppm
Agent concentration
(concentration before 8—month preservation and immediately after preparation)
(b)
Coxsackievirus B5-inactivation eFFect
g 6 (10 ppm: concentration before 8-month preservation and immediately after preparation)
I—l
°° "'"'""I'"‘------l---------||
2 5 Agent C (Na hypochlorite)
o
m 4 Agent B (containing organic acid)
Q
g 8 Agent A (containing inorganic acid salt)
2 l l l
O minutei 1 minute 2 minutes 3 minutes
Sensitized time
US. Patent
Oct. 1, 2013 Sheet 4 0f 7 US 8,545,898 B2
Fig.4
TCID50(log10) .50
AIDS virus—inactivation etFect (sensitized time: 1 minute)
Agent D
.00
_ _ (stabilized chlorine dioxide)
.50
.00
Agent B
(containing organic acid)
.50
.00
Agent 0
(Na hypochlorite)
.50
.00
.50
.00
Agent A (containing inorganic acid salt)
.50
O. O 1 O. 1 1 1 O 1 O 0
Agent concentration
(concentration before 8~month preservation and immediately after preparation) DPm
US. Patent 0a. 1, 2013 Sheet 5 0f7 US 8,545,898 B2
Fig.5
Human hepatitis B surface antigen (HBsAg)-inactivation effect
6 O (100 ppm: concentration before 8—month preservation and at preparation)
_ _-_ Agent 0
5O _-------""" ‘~._ (Nahypochiorite)
_ "I
~
N
e *~
5 I
5 4 O
E
E 3 0 Agent B (containing organic acid)
U) A A
E v v u 0
g
2 O
l 0
Agent A (containing inorganic acid salt)
0
O 1 2 3 4
Sensitized time (day)
US. Patent 0a. 1, 2013 Sheet 6 0f7 US 8,545,898 B2
Fig.6
Canine parvovirus CPVlY—l)~inactivation effect
(100 ppm: concentration before 8-month preservation and at preparation)
5. 00
¢ 0‘ ~ ~ _
’ ’ _ _ _ ~ ~
I ~ ~
4 50 -O- *0 <> - - _ _ _
A Agent D (stabilized chlorine dioxide)_ 0
Si
O 4. 00
H \
V i
o 3. 50 \
LO \
Q \
H ‘
U 3. 00 l
[-i
2 50 \ Agent B (containing organic acid)
\U \J U
2 00 ‘
\
\
\
1. 5O \
\
\
\
l. 00 \
.~ - _ _ _ Agent 0 (Na hypochlorite)
0_ 50 ‘4 t ‘ ‘
Agent A (containing inorganic acid salt)
I l l l l l
O 30 60 90 120 150 180
Sensitized time (second)
US. Patent 0a. 1, 2013 Sheet 7 0f7 US 8,545,898 B2
Fig.7
Rotavirus—inactivation effect
1 2 O (1ppm: concentration before 8-month preservation and at preparation)
1 O 0
g
= 8 O
(D
o
B
*5 6 0 Agent B (containing organic acid)
HGE’ v 6 @
Lg
2 4 O
4.:
(U
D:
2 0
Agent A (containing inorganic acid salt)
0 a ’ L
0 50 100 150 200
Sensitized time (second)
US 8,545,898 B2
1 2
BROAD-SPECTRUM ANTIVIRAL bon dioxide gas is not rapidly generated, and a desired phar
COMPOSITION WITH EXCELLENT macological activity is sustained by maintaining the chlorine
PRESERVATION STABILTY dioxide concentration constant for a long term. In addition,
even when dissolved chlorine dioxide is continuously
TECHNICAL FIELD released by portions as chlorine dioxide gas, the chlorine
dioxide concentration can be held in an approximately con
The present invention relates to a composition for a broad stant range.
spectrum antiviral agent (hereinafter also simply referred to Patent Document 1: Japanese Patent Application JP61
as “antiviral composition”) with excellent preservation sta 1 81532A
bility. Particularly, the present invention relates to an antiviral Patent Document 2: Japanese Patent JP3110724B
composition for an agent including chlorine dioxide dis
solved therein, in which an antiviral activity is steadily DISCLOSURE OF THE INVENTION
retained for a long term, speci?cally, a pharmacological activ
ity of chlorine dioxide during preservation does not change, The present inventors made intensive and extensive studies
and a chlorine dioxide concentration is not reduced even with the view towards ?nding a novel clinical application of
when dissolved chlorine dioxide dissipates by portions as the chlorine dioxide solution including safe application to
chlorine dioxide gas during long-term preservation. human being, which would be possible due to the improved
preservation stability and controllable concentration. As a
BACKGROUND ART result, they discovered that the chlorine dioxide solution sur
20 prisingly exerts an inactivation effect against a wide range of
As is well known, chlorine dioxide gas is a strong oxidant, viruses including a mucocutaneous infector virus, and that the
and because its oxidizing action is effective in sterilization solution retains an excellent potency (virus-inactivation
and decomposition of malodorous substances, chlorine diox potency) even after long-term preservation (for instance, after
ide gas has been used in disinfectant, deodorant and the like. l-year preservation in a container), and based on these ?nd
The chlorine dioxide gas is dissolved in water in 20 times its 25 ings, they completed the present invention.
volume of water, to give a brown aqueous solution. From the Accordingly, the present invention provides a composition
viewpoint of easiness in handling, it is desirable to use chlo for a broad-spectrum antiviral agent with excellent preserva
rine dioxide in a form of such an aqueous solution. tion stability, which includes a chlorine dioxide solution.
When the aqueous solution of chlorine dioxide is brought To attain the above-described purpose, in a ?rst aspect of
into contact with air, chlorine dioxide gas is rapidly gener 30 the present invention, there is provided a composition for a
ated. Therefore, there has been proposed a technique in which broad-spectrum antiviral agent with excellent preservation
chlorine dioxide gas is constantly generated while maintain stability which includes a pure chlorine dioxide solution
ing its stability, by dissolving chlorine dioxide gas in an including: a chlorine dioxide gas dissolved therein; a chlorite;
aqueous solution of sodium peroxycarbonate, and thus by and a pH adjuster.
forming an aqueous solution containing sodium chlorite as a 35 In a second aspect of the broad-spectrum antiviral compo
main component with retained alkalinity (pH 9), i.e., what is sition with excellent preservation stability of the present
called a stabilized aqueous solution of chlorine dioxide (see invention, the chlorite is sodium chlorite, and the pH adjuster
Patent Document 1). is an inorganic acid or a salt thereof having a buffering prop
However, when the alkalinity is retained in the stabilized erty.
aqueous solution of chlorine dioxide, a generation amount of 40 In a third aspect of the broad-spectrum antiviral composi
free chlorine dioxide gas having disinfecting and deodorizing tion with excellent preservation stability of the present inven
effects or the like is extremely low, and thus the solution has tion, the chlorite is sodium chlorite, and the pH adjuster is
a low pharmacological activity. Accordingly, it is dif?cult to phosphoric acid or a salt thereof.
attain satisfactory disinfecting and deodorizing effects or the In a fourth aspect of the broad-spectrum antiviral compo
like. 45 sition with excellent preservation stability of the present
Therefore, in order to enhance the pharmacological activ invention, the chlorite is sodium chlorite, and the pH adjuster
ity of the stabilized aqueous solution of chlorine dioxide, an is sodium dihydrogenpho sphate or a mixture of sodium dihy
acid has been added immediately before its use to lower the drogenphosphate with sodium monohydrogenphosphate.
pH to 7 or less, for generating chlorine dioxide gas. The antiviral composition of the present invention has an
However, with this technique in which an acid is added 50 inactivation effect on a wide range of viruses, and though it
immediately before its use, there arise economical problems contains chlorine dioxide, exhibits excellent preservation sta
that processes and equipments or facilities to implement the bility, and the viral inactivation effect is sustained after long
processes are required in order to enhance the pharmacologi term preservation.
cal activity of the stabilized aqueous solution of chlorine
dioxide. In addition, since chlorine dioxide gas is rapidly 55 BRIEF DESCRIPTION OF DRAWINGS
generated as a result of the addition of acid, it is dif?cult to
expect a sustained pharmacological activity of the stabilized FIG. 1 is a graph showing an in?uenza virus-inactivation
aqueous solution of chlorine dioxide. Moreover, a pharmaco effect of the broad-spectrum antiviral composition of the
logical activity is not retained constant and sometimes present invention.
reaches an extremely high level, which raises safety concern 60 FIG. 2 is a graph showing a norovirus (feline calicivirus as
about effects on animals, especially on human being. a surrogate)-inactivation effect of the broad-spectrum antivi
In order to solve the above-mentioned problems, there has ral composition of the present invention.
been proposed a technique in which a mixture prepared by FIG. 3 shows graphs indicating a coxsackievirus B5-inac
adding an organic acid, such as citric acid, to chlorite is tivation effect of the broad-spectrum antiviral composition of
blended with a dissolved chlorine dioxide solution, to thereby 65 the present invention in which (a) represents a case where the
maintain a chlorine dioxide concentration nearly constant for sensitized time is 1 minute, and (b) represents a case where
a long term (see Patent Document 2). In this technique, car the concentration is 10 ppm.