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.degree. 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
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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.degree. 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
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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
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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.degree. 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
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Percent Percent
Agent for imparting
remainder remainder
appropriate consistency
of available
of sugar Consistency
and stability iodine (%)
(%) (appearance)
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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
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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.
