BACKGROUND OF THE
INVENTION
(i) Field of the Invention:
This invention relates to stable
external medicinal preparations useful for the
healing of damaged skin (hereinafter abbreviated
as "wounds" for the sake of brevity) such as
burns, decubitus and open wounds. More
specifically, it is concerned with wound-healing
preparations which contain a sugar and
povidone-iodine (polyvinylpyrrolidone-iodine
complex) as effective ingredients.
(ii)
Description of the Prior Art:
Sugars
such as honey and molasses have conventionally
been used, as folk therapy, for the treatment of
burns and open wounds. These sugars have also
been known to have bacteriostatic action and
granulation tissue growth-promoting effects.
Povidone-iodine is a drug employed extremely
widely as an antiseptic throughout the world.
It has recently been reported that
excellent wound-healing effects were achieved
when granulated sugar was mixed with
povidone-iodine preparations such as "Betadine"
(trade mark of The Purdue Frederick Co.,
Norwalk, Connecticut, U.S.A.) ointment,
"Betadine" solution and "Isodine Gel" (trade
mark; product of Meiji Seika Kaisha, Ltd.,
Tokyo, Japan) and the resultant mixtures were
applied to various wounds [R.A. Knutson et al.,
"Southern Medical Journal", 74(11), 1329-1335
(1981); and Kiyokazu Sone et al., "Byoin
Yakugaku (Hospital Pharmacology)", 10(5),
315-322 (1984)].
Further, Japanese
Patent Application Laid-Open No. 141409/1980 of
Nov. 5, 1980, which corresponds in part to U.S.
Pat. No. 4,401,651 issued on Aug. 30, 1983,
discloses a composition composed of 20 parts by
weight of granulated sugar, 5 parts by weight of
"Betadine" ointment and 2 parts by weight of
"Betadine" solution. Although "Betadine"
ointment and solution are povidone-iodine
preparations produced and marketed in U.S.A. by
The Purdue Frederick Co., they are not
commercially available in Japan. Details of
their ingredients are hence unknown to the
present inventors.
The following
problems were however found on compositions,
which had been prepared respectively by mixing
commercial povidone-iodine preparations
available to the present inventors with a sugar
in accordance with the formulation described in
Japanese Patent Application Laid-Open No.
141409/1980 referred to above.
(1) The
content of povidone-iodine in each of the
commercial povidone-iodine preparations was not
constant. The ratio of the sugar to
povidone-iodine in the resulting composition
hence varied from one production lot to another,
whereby it was difficult to obtain compositions
of uniform quality.
(2) The mixture of
each of the commercial povidone-iodine
preparation and the sugar has an extremely high
viscosity. A special apparatus was therefore
needed to perform uniform kneading. Furthermore,
it was difficult to produce the composition in a
large volume by a single mixing operation.
(3) When stored at room temperature,
each of the compositions separated into two
layers or was rendered like starch syrup and
moreover, its effective ingredient underwent
decomposition to reduce the drug efficacy. It
was thus necessary to store the compositions in
a cool and dark place. The effective ingredient
was however decomposed in several months even
when stored in the above manner. It was hence
essential to prepare the compositions before
use.
Among these problems, the problem
(3) which requires the preparation of a
composition before use is an extremely serious
problem. The problem (3) has therefore led to
such inevitable drawbacks that the composition
cannot be prepared except for large hospitals
equipped, for example, with the above-mentioned
kneader, aseptic manipulation facilities,
sterilization equipment and the like and
patients must attend hospitals whenever
administration is required.
SUMMARY OF
THE INVENTION
An object of this
invention is to provide a wound-healing
preparation which can be formulated with a
uniform composition by a simple operation and
moreover, can be stored stably over a long
period of time.
The present inventors
have thus carried out an extensive investigation
to achieve the above object of this invention.
As a result, it has been found that a stable
preparation, which has overcome the
above-described problems, can be obtained by
using povidone-iodine in place of such a
povidone-iodine preparation, mixing
povidone-iodine, a sugar and water at a
predetermined ratio and adjusting the pH of the
resultant mixture to a specific level with a
buffer. The present inventors have also found
that an incorporation of a polysaccharide or its
derivative as an agent for imparting an
appropriate consistency and stability in the
above stable preparation can provides a more
stable preparation which does not undergo phase
separation even when stored over a long period
of time.
In one aspect of this
invention, there is thus provided a
wound-healing preparation which comprises 50 -90
wt.% of a sugar, 0.5-10 wt.% of povidone-iodine,
1-20 wt.% of water and a buffer in an amount
sufficient to adjust the pH of the preparation
to 3.5-6.
In another aspect of this
invention, there is also provided a
wound-healing preparation which comprises 50-90
wt.% of a sugar, 0.5-10 wt.% of povidone-iodine,
1-20 wt.% of water, 0.1-5 wt.% of an agent for
imparting an appropriate consistency and
stability selected from polysaccharides and
derivatives thereof, and a buffer in an amount
sufficient to adjust the pH of the preparation
to 3.5-6.
The preparation of this
invention is extremely easy to produce and is
stable over a long period of time. It can thus
be filled in opaque containers for practical
use.
BRIEF DESCRIPTION OF THE DRAWING
The above and other objects, features
and advantages of the present invention will
become apparent from the following description
and the appended claims, taken in conjunction
with the accompanying sole drawing,
FIG.
1, which diagrammatically illustrates the
relationship between the stability of aqueous
solutions of povidone-iodine and a sugar and
their pH .
DETAILED DESCRIPTION OF THE
INVENTION AND PREFERRED EMBODIMENTS
The
sugar, which is to be used in this invention,
must be a non-reducing sugar. Sucrose, glucose,
dextrose, honey, molasses, etc may be mentioned
by way of example. Among these, sucrose and
purified sucrose specified in The Japan
Pharmacopoeia are particularly preferred in
order to obtain compositions of uniform quality.
On the other hand, it is possible to use, as
povidone-iodine, that described in the Standard
for Quasi-Drug Ingredients, The Japan
Pharmacopoeia.
The proportion of the
sugar is 50-90 wt.% (hereinafter referred to
merely by "%") of the whole composition with
60-80% being preferred. The proportion of
povidone-iodine ranges from 0.5%, the minimum
proportion requires for the exhibition of
bacteriostatic action, to 10%. Water is added in
an amount of 1-20% with 1-15% being preferred.
As illustrative examples of the
polysaccharide or its derivative which is an
agent for imparting an appropriate consistency
and stability, dextrin, gum arabic, pullulan,
chondroitin sulfate, methylcellulose, sodium
carboxymethylcellulose an the like may be
mentioned. These polysaccharides and their
derivatives show specific effects for the
stability of the preparation. Other agents which
are also employed generally for the same purpose
cannot achieve sufficient effects or on the
contrary, give some deleterious effects to the
stability. Such an agent may preferably be added
in an amount of 0.1-5%, notably, 0.1-3% based on
the whole composition.
In addition to
these essential ingredients, it is also possible
to incorporate a routine excipient and a
povidone-iodine solubilizer as needed.
Illustrative examples of the solubilizer may
include potassium iodide, sodium iodide,
glycerin and the like. As exemplary excipients,
may be mentioned glycols such as polyethylene
glycol 400, 1500, 4000 and 6000, polyoxyethylene
polyoxypropylene glycol and polypropylene
glycol; glycerins such as glycerin and
polyglycerin; polyoxyethylene-hardened castor
oil; polyoxyethylene polyoxypropylene block
polymer; etc.
When the preparation of
this invention is added with the above-described
ingredients only, its effective ingredients,
i.e., the sugar and povidone-iodine are
instable. It is hence necessary to adjust its
pH. Namely, a composition consisting of 80% of
granulated sugar, 3% of povidone-iodine and 17%
of water was prepared. Using a 0.1 M disodium
phosphate-citrate buffer, portions of the
composition were adjusted to various pH levels
respectively. They were stored at 40° C. for 2
weeks. The percentages of the sugar remaining in
the respective samples were measured by high
performance chromatography, while the
percentages of povidone-iodine remaining in the
respective samples were measured by titration.
Results are diagrammatically illustrated in FIG.
1. As apparent from the above experiment, it is
within a range of pH 3.5-pH 6 that the sugar and
povidone-iodine are both stable.
As a
buffer capable of adjusting the pH of the
preparation of this invention to such a level,
may be mentioned by way of example a lactate
buffer, citrate buffer, phosphate buffer,
potassium hydrogenphthalate buffer or the like.
No particular limitation is imposed on
the production method of the preparation of this
invention. For example, it may be produced by
dissolving povidone-iodine and a solubilizer
therefor in a buffer, adding and mixing an
aqueous solution of a sugar either alone or
together with an aqueous solution of an agent
for imparting an appropriate consistency and
stability, both solutions having been prepared
separately, and optionally adding an excipient
to adjust the viscosity.
Having
generally described the invention, a more
complete understanding can be obtained by
reference to certain specific examples, which
are provided herein for purposes of illustration
only and are not intended to be limiting unless
otherwise specified.
EXAMPLES
The present invention will hereinafter
be described by the following Examples.
EXAMPLE 1
______________________________________
parts by weight
______________________________________
(1) Povidone-iodine 3
(2) 0.1 M lactic acid-sodium
11
lactate buffer (pH 5.5)
(3) Potassium iodide 0.9
(4) Purified sucrose 70.7
(5) 1 N sodium hydroxide solution
1.2
(6) Polyethylene glycol 400
9
(7) Polyethylene glycol 6000
2.6
(8) Polyoxyethylene polyoxy-
1
propylene glycol
(9) Glycerin 0.6
______________________________________
To a solution of the ingredients
(1) and (3) dissolved in the ingredient (2), the
ingredients (5) and (4) were added and mixed. A
mixture of the ingredients (6), (7), (8) and
(9), which had been prepared separately, was
added gradually to the former mixture so that
all the ingredients were kneaded into a
homogeneous preparation.
Test 1:
The invention product prepared in
Example 1, Hospital Formulation I ["Gekkan
Yakuji (The Pharmaceuticals Monthly)", 25(7), 97
(1983)] and Hospital Formulation II ["Gekkan
Yakuji (The Pharmaceuticals Monthly)", 25(5),
129 (1983)], the latter two being conventional
products, were heated to 60° C. to measure pH
variations and the percentages of available
iodine and sugar remaining therein. Results are
summarized in Tables 1-3.
______________________________________
Hospital Formulation I:
Granulated sugar 72.4%
Isodine Gel 21.0
Isodine Solution 6.6
Hospital Formulation II:
Granulated sugar 57.1%
Simple syrup 17.2
Isodine Gel 25.7
______________________________________
TABLE 1
______________________________________
(pH)
Hospital Hospital
Invention Formula- Formula-
product tion I tion II
______________________________________
Initial 5.14 4.20 4.12
3 Days later
4.27 3.57 2.78
6 Days later
4.18 2.68 2.53
9 Days later
4.16 2.67 2.68
______________________________________
TABLE 2
______________________________________
(Available Iodine, %)
Hospital Hospital
Invention Formula- Formula-
product tion I tion II
______________________________________
Initial 100 100 100
3 Days later
94.6 96.9 61.0
6 Days later
93.4 30.1 0
9 Days later
91.4 0 0
______________________________________
TABLE 3
______________________________________
(Sugar, %)
Hospital Hospital
Invention Formula- Formula-
product tion I tion II
______________________________________
Initial 100 100 100
3 Days later
100.7 91.5 40.8
6 Days later
98.5 25.2 5.5
9 Days later
97.7 5.5 0
______________________________________
EXAMPLE 2
A preparation of
the following composition was formulated in the
same manner as in Example 1.
______________________________________
parts by weight
______________________________________
Povidone-iodine 3
0.1 M citrate buffer (pH 5.3)
11
Potassium iodide 0.9
Purified sucrose 65
1 N sodium hydroxide
1
Polyethylene glycol 400
8
Polyethylene glycol 1500
7.3
Polyoxyethylene polyoxy-
2.8
propylene glycol
Glycerin 1
______________________________________
EXAMPLE 3
______________________________________
parts by weight
______________________________________
(1) Povidone-iodine 3
(2) 0.05 M citrate buffer (pH 5.3)
8.9
(3) Potassium iodide 0.7
(4) Purified sucrose 70
(5) Agent for imparting an
0.5
appropriate consistency
and stability
(6) 1 N sodium hydroxide
0.8
(7) Polyethylene glycol 400
14
(8) Polyoxyethylene polyoxy-
1.1
propylene glycol
(9) Glycerin 1.0
______________________________________
To a solution of the ingredients
(1) and (3) dissolved in the ingredient (2), the
ingredients (6) and (4) were added and mixed. A
mixture of the ingredients (5), (7), (8) and
(9), which had been prepared separately, was
added gradually to the former mixture, so that
all the ingredients were kneaded into a
homogeneous preparation.
Test 2:
After the preparations formulated in
Example 3 with different agents (5) shown below
in Table 4 were stored at 40° C. for 3 months,
the percentages of available iodine and sugar
remaining in the respective preparations were
measured and the consistency of the preparations
were also observed. Results are summarized in
Table 4.
TABLE 4
______________________________________
Percent Percent
Agent for imparting
remainder remainder
appropriate consistency
of available
of sugar Consistency
and stability iodine (%)
(%) (appearance)
______________________________________
Invention preparation
Pullulan 92 98 Unchanged
Dextrin 86 98 "
Gum arabic 87 100 "
Chondroitin sulfate
82 100 "
Methylcellulose
82 97 "
Sodium carboxymethyl-
85 98 "
cellulose
Avicel (trade mark)
81 97 "
Comparative preparation
Albumin 60 80 "
Sodium casein 55 80 "
Gelatin 65 90 "
Poly(sodium acrylate)
48 96 Rubbery
______________________________________
EXAMPLE 4
______________________________________
parts by weight
______________________________________
(1) Povidone-iodine 3
(2) 0.1 M lactic acid-sodium
11.0
lactate buffer (pH 5.5)
(3) Potassium iodide 0.9
(4) Purified sucrose 70.7
(5) Pullulan 0.6
(6) 1 N sodium hydroxide solution
1.2
(7) Polyethylene glycol 400
9
(8) Polyethylene glycol 6000
2
(9) Polyoxyethylene polyoxy-
1
propylene glycol
(10) Glycerin 0.6
______________________________________
To a solution of the ingredients
(1) and (3) dissolved in the ingredient (2), the
ingredients (6) and (4) were added and mixed. A
mixture of the ingredients (5), (7), (8), (9)
and (10), which had been prepared separately,
was added gradually to the former mixture, so
that all the ingredients were kneaded into a
homogeneous preparation.
Having now
fully described the invention, it will be
apparent to one of ordinary skill in the art
that many changes and modifications can be made
thereto without departing from the spirit and
scope of the invention as set forth herein.
* * * * *
United States Patent 4844898
