JP2000038342A - Pharmaceutical preparation for restoring bedsore and damaged skin - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a pharmaceutical preparation for restoring bedsore and damaged skin in the form of an ointment containing active ingredients such as refined sugar and povidone-iodine having stability for a long period without using a shape retaining agent or a buffer agent, having extensibility and excellent in feeling of use. SOLUTION: This pharmaceutical preparation for restoring bedsore and damaged skin contains 0.5-5.0 wt.% of at least one kind selective from the group consisting of a lithium salt, a sodium salt, a magnesium salt, a potassium salt, a calcium salt, a zinc salt and an ammonium salt of alginic acid or the salts of a derivative of polysaccharides represented by the following formula [R1, R2 and R3 may each be same or different and at least one kind thereof is carboxymethyl group; the remaining groups are each hydrogen atom, methyl group or ethyl group; the bond between mutual pyranose rings may be an α-1,4 bond or a β-1,4 bond; (n) is a natural number] as a stabilizer in the pharmaceutical preparation for restoring the bedsore and damaged skin containing 50-90 wt.% of a sugar, 0.5-10 wt.% of povidone-iodine and 1-20 wt.% of water.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a stable external pharmaceutical preparation used for repairing pressure ulcers and damaged skin.
More specifically, the present invention relates to an ointment-like preparation for repairing decubitus / damaged skin containing sugar and povidone-iodine as active ingredients.

[0002]

2. Description of the Related Art It has been generally known that sucrose has a wound healing action and povidone-iodine has a bactericidal action.
It has been reported that when povidone-iodine drug such as isodine gel (trade name of Meiji Seika Co., Ltd.) is mixed with granulated sugar and applied to various damaged skins, an excellent skin repair effect was obtained [Hospital Pharmacy, Dai Volume 10, Issue 3
15-322 (1984)]. However, sucrose is hydrolyzed under acidic conditions and gradually changes into invert sugar (one molecule of glucose and one molecule of fructose). Povidone-iodine is decomposed by the reducing action of invert sugar, so that the effectiveness of sucrose and povidone-iodine can be maintained for a long time. A formulation was sought.

As a povidone-iodine preparation which can be stored stably for a long period of time, Japanese Patent Publication No. 1-321010 discloses a sugar 50 to 9
0% by weight, 0.5-10% by weight of povidone-iodine, 1% of water
Damaged skin containing 20% by weight and a buffer for adjusting the pH of the preparation to 3.5 to 6, and further containing 0.1 to 5% by weight of a shape-retaining agent selected from polysaccharides or derivatives thereof. Restorative formulations have also been reported. However, the preparation described in the publication does not have sufficient extensibility to gauze or the like when used for daily treatment, and for a patient who has pressed it against the damaged skin surface, a foreign body sensation is felt in the contact affected area. It is the current situation to remember. Therefore, in the field of treatment, there is a demand for an easy-to-use preparation that can be easily spread on gauze or the like and has no foreign-body sensation even when pressed against an affected part of a patient.

On the other hand, as a solution which can avoid the problem of extensibility, a technique for powdering a povidone-iodine preparation, that is, 50-90% by weight of sugar, 0.5-10% by weight of povidone-iodine, and polyvinyl alcohol, polyvinylpyrrolidone , Polyacrylic acid, or a salt thereof, pullulan, carboxymethylcellulose, hydroxypropylmethylcellulose, and a water-soluble polymer carrier selected from carboxymethylcellulose or a salt thereof have been proposed as a powder preparation for repairing damaged skin (Japanese Patent Application Laid-Open No. 8-12882). No.).

[0005] Since the powder formulation can be applied by spraying, the problem of extensibility can be avoided, and since it can be used without directly applying to the affected part, there is an effect that the affected part is less likely to be damaged. However, the stability and therapeutic effect of such powder preparations have not been confirmed.

[0006] The present invention has been made in view of such circumstances, and it is an object of the present invention to provide an active ingredient such as sucrose and povidone-iodine which has long-term stability and is extensible. An object of the present invention is to provide an ointment-like preparation for pressure ulcer / damaged skin which is excellent in feeling.

[0007]

Means for Solving the Problems The present inventors have conducted intensive studies on stabilizing agents capable of stably retaining active ingredients such as sucrose and povidone-iodine for a long period of time without using a shape-retaining agent or a buffer. Was completed.

That is, the preparation for repairing pressure ulcer / damaged skin of the present invention comprises 50 to 90% by weight of sugar and 0.5 to 50% by weight of povidone iodine.
In a preparation for pressure ulcer / damaged skin repair containing 10% by weight and 1 to 20% by weight of water, as a stabilizer, lithium salt, sodium salt, magnesium salt, potassium salt, calcium salt, zinc salt and ammonium salt of alginic acid It is characterized by containing at least one, preferably a monovalent salt of alginic acid, selected from the group consisting of 0.5 to 5.0% by weight. Alternatively, as a stabilizer, at least one selected from the group consisting of lithium salts, sodium salts, magnesium salts, potassium salts, calcium salts, zinc salts, and ammonium salts of a polysaccharide derivative represented by the following formula, preferably Represents a monovalent salt of the polysaccharide derivative in the range of 0.5 to 5.0.
% By weight.

[0009]

Embedded image

(Wherein R ₁ , R ₂ , and R ₃ may be the same or different, at least one is a carboxymethyl group, the rest is a hydrogen atom, a methyl group, or an ethyl group; Is α-1,4 bond, β-
(It may be 1, 4 bonds, and n is a natural number.) It is preferable that the preparation for repairing decubitus / damaged skin of the present invention does not contain a metal hydroxide.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The sugar used in the present invention is a non-reducing sugar, such as sucrose, glucose, honey, molasses, etc. Among them, sucrose and purified sucrose described in the Japanese Pharmacopoeia are preferable. Particularly, purified sucrose is preferred. The content of sugar in the preparation is 50 to 90% by weight, preferably 60% by weight.
~ 80% by weight.

[0012] Povidone-iodine is a complex of a polymer of 1-vinyl-2-pyrrolidone and iodine, and the one described in the Japanese Pharmacopoeia may be used. The content of povidone-iodine in the whole preparation is from 0.5% by weight to 10% by weight, which is the minimum amount capable of exhibiting bactericidal activity.

Water is incorporated in an amount of 1 to 20% by weight. An ointment-like preparation can be obtained by incorporating water in such an amount.

The stabilizer used in the present invention satisfies the condition of pH 5.5 or higher so that the whole preparation can be adjusted to the optimum pH of 3.5 to 6.0 with a small amount of addition. Among the stabilizers described above, those which can exhibit the stability of sucrose and effective iodine to the same extent or higher than those of conventional preparations.

[0015] A stabilizer which can satisfy such conditions is:
It is a salt of alginic acid or a salt of a polysaccharide derivative represented by the following formula.

[0016]

Embedded image

(Wherein at least one of R ₁ , R ₂ and R ₃ is —CH ₂ COOH, the rest is a hydrogen atom, a methyl group or an ethyl group, and the bond of pyranose is α-
Alginic acid may be mainly 1,3-D-mannuronic acid or α-1,4-L-guluronic acid. A linear polysaccharide composed of two uronic acids, where only mannuronic acid is 1,
A block formed by 4-glycosidic bonds (M block),
A block heteropolymer in which any one of a block in which only guluronic acid is 1,4-glycosidically bonded (G block) and a block in which mannuronic acid and guluronic acid are randomly arranged (random block) may coexist. , The ratio of M block to G block, and the ratio of mannuronic acid and guluronic acid in the random block are not particularly limited. Therefore, alginic acid extracted from various brown algae corresponds. The degree of polymerization and molecular weight of alginic acid are not particularly limited, but alginic acid having a molecular weight of 50,000 to 200,000 is generally used.

The alginate used in the present invention is a salt of such alginic acid, in which the carboxyl group in the molecule of mannuronic acid and guluronic acid is converted into a salt, such as lithium alginate, sodium alginate and potassium alginate. Divalent metal salts; divalent metal salts such as calcium alginate, magnesium alginate, zinc alginate;
Ammonium alginate and the like; among these, lithium alginate which is a monovalent salt of alginic acid;
Sodium alginate, potassium alginate and ammonium alginate are preferably used, and more preferably sodium alginate is used. This is because a monovalent salt has a higher stabilizing effect as a stabilizer.

The polysaccharide derivative is β1 of glucopyranose.
→ at least one of the hydrogens of the hydroxyl group of the cellulose derivative as a chain polymer by a 4 glucoside bond or the α1 of glucopyranose as a chain polymer by a 4 glucoside bond is a carboxymethyl group,
The remainder refers to those having a hydrogen atom (corresponding to a state in which a hydroxyl group is not substituted) or a methyl group or an ethyl group. The degree of substitution of the carboxymethyl group and the degree of substitution of the methyl group or the ethyl group are not particularly limited. Specific examples of such polysaccharide derivatives include cellulose derivatives such as carboxymethylcellulose and carboxymethylethylcellulose; and starch derivatives such as carboxymethyl starch. The degree of polymerization (n) and molecular weight of these polysaccharide derivatives are not particularly limited, but are generally about 100 to 2000, preferably 1 to 2.
It is about 00 to 1000, more preferably about 300 to 700.

The salt of such a polysaccharide derivative means that the carboxyl moiety in the carboxymethyl group is a lithium salt,
Sodium, potassium, magnesium, calcium, zinc and ammonium salts, specifically, sodium carboxymethylcellulose (C
MC-Na), potassium carboxymethylcellulose (CMC-K), calcium carboxymethylcellulose (CMC-Ca), ammonium carboxymethylcellulose, sodium carboxymethylethylcellulose, potassium carboxymethylethylcellulose, calcium carboxymethylethylcellulose, sodium carboxymethylstarch (CMS-Na) ), Carboxymethyl starch potassium, carboxymethyl starch ammonium, carboxymethyl starch calcium and the like. Among these, monovalent salts such as lithium salt, sodium salt, potassium salt and ammonium salt are preferable, and sodium salt is more preferable. This is because a monovalent salt, particularly a sodium salt, has a high stabilizing effect as a stabilizer.

These stabilizers may be used alone or in combination of two or more, but it is preferable to use only one type alone. Since these alginates themselves have a hemostatic effect and have a granulation-reforming effect, from such a meaning, it is possible to expect a damaged skin repair effect as a preparation for pressure ulcer / damaged skin repair. This is because these alginates have water absorbency, so that exudates from pressure ulcers can be absorbed, and promotion of the skin repair effect by sucrose and povidone-iodine can be expected.

[0022] The above-mentioned stabilizer is used in the preparation in an amount of 0.5%.
% By weight, preferably 1.0% by weight or more, more preferably 1.5% by weight or more and 5.0% by weight or less, preferably 2.5% by weight or less. If the amount is less than 0.5% by weight, the effect as a stabilizer is not sufficient, so that the stability of effective iodine or sucrose in the preparation cannot be obtained. On the other hand, if the content exceeds 5% by weight, the preparation becomes hard and the extensibility decreases.

The preparation of the present invention may contain, if necessary, a commonly used excipient, a solubilizing agent for povidone-iodine, in addition to the above essential components.

Examples of the excipient include glycols such as polyethylene glycol 400, 1500, 4000, 6000, polyoxyethylene polyoxypropylene glycol, and polypropylene glycol; glycerin,
Glycerin such as polyglycerin; polyoxyethylene hydrogenated castor oil; polyoxyethylene polyoxypropylene block polymer;

Examples of the solubilizer include potassium iodide, sodium iodide, glycerin and the like.

The formulation of the present invention does not exclude the components other than the above components, but the above components alone can satisfy the stability of sucrose and effective iodine. Therefore, it is not necessary to contain a buffer or an alkaline compound (specifically, a hydroxide of an alkali metal such as NaOH or KOH) for adjusting the pH of the preparation to 3.5 or more. In addition, a stable preparation that can be stored for a long period of time without causing phase separation even without adding a shape-retaining agent can be obtained. Further, although the reason is not clear, the formulation of the present invention, which does not contain a buffer or a shape-retaining agent and satisfies the stability with a stabilizer, has an elongation (extensibility) upon application and a smoothness of the formulation. , Etc., was slightly better than conventional products. Furthermore,
When using a metal salt of alginic acid as a stabilizer, particularly sodium alginate or calcium alginate,
Due to the hemostasis effect, granulation regeneration effect, and water absorption effect of the stabilizer itself, a more excellent effect of repairing pressure ulcer and damaged skin can be expected.

The method for producing the preparation of the present invention is not particularly limited. For example, there is a method in which povidone-iodine and a stabilizer are mixed with purified water to prepare an aqueous solution of povidone-iodine, and sucrose is added to the aqueous solution to mix uniformly. No. When a solubilizing agent or a shaping agent is mixed, it may be added and mixed when preparing an aqueous solution of povidone-iodine, or may be added and mixed with the prepared aqueous solution.

[0028]

[Example] [Measurement method] Measurement of pH Purified water was added to 1 g of a sample, and an aqueous solution having a total volume of 10 ml was measured using a pH meter (manufactured by HORIBA).
It was measured based on the pH measurement method of the Japanese Pharmacopoeia General Test Method.

An effective iodine sample (5 g) was precisely weighed, dissolved in 40 ml of purified water, and redox titrated with a 0.01 N sodium thiosulfate solution using 2 ml of a starch sample as an indicator according to Scotts Standard Methods. The amount of available iodine was determined. A solution containing no iodine as a blank was similarly titrated, and the amount of iodine in the blank was corrected to determine the amount of effective iodine in the sample. In addition, 0.01mo
1 ml of 1 / l sodium thiosulfate solution is 1.2690
mg of iodine.

Assuming that the amount of iodine immediately after preparation is 100%, it is expressed as a residual rate (%) at the time of sampling.

Sucrose A sample was weighed in an amount of 0.245 g of purified sucrose, dissolved in purified water, an internal standard solution was further added, water was further added to make the whole 50 ml, and the mixture was filtered through a membrane filter. The obtained filtrate was used as a sample solution, and a liquid chromatographic test was performed to determine a peak height ratio (Q _T ). Separately, 0.245 g of purified sucrose was weighed and dissolved in purified water, and then an internal standard solution was further added.
A liquid chromatographic test was performed in the same manner as described above, and the height ratio of peaks (Q _S ) was determined, and the amount of sucrose was determined by the following equation. The amount of sucrose = 0.245 g × Q _T / Q _{S The} amount of sucrose immediately after preparation is defined as 100%, and expressed as the residual rate (%) at the time of sampling.

[Selection of Stabilizer] Formulations a to f using sodium alginate, sodium carboxymethylcellulose (CMC-Na), DL-alanine, sodium caseinate, urea, magnesium chloride as a stabilizer having a pH of 5.5 or more. The stability of pH, the stability of sugar, and the stability of available iodine were investigated. For the sake of comparison,
The stability of pH, the stability of sucrose, and the stability of effective iodine of the preparation described in Japanese Patent Publication No. 10 were examined.

The composition of each preparation was as shown in Table 1 and was prepared as follows.

[0034]

[Table 1]

That is, povidone iodine, potassium iodide, polyoxyethylene polyoxypropylene glycol (POEPOPG), a stabilizer, and a buffer (0.05M citrate buffer) in the case of the conventional example were added to purified water. And stir well, then add polyethylene glycol 40
0 (PEG) and glycerin were added and stirred. Into the kneading machine, put purified sucrose (in the case of the conventional example, further sodium hydroxide), add the povidone-iodine solution prepared above,
A shape-retaining agent (pullulane) was gradually added and uniformly kneaded to obtain a preparation.

Among the obtained preparations, the preparations (e, f) using urea and magnesium chloride as stabilizers showed remarkable deterioration in syrup. Other preparations (conventional example and a
-D) was stored at 50 ° C. and 75% for 54 days, and immediately after the preparation, the pH, the sucrose,
It was measured for available iodine.

Table 2 shows the measurement results.

[0038]

[Table 2]

As can be seen from Table 2, the formulations a to f
In any case, the pH at the time of preparation can be adjusted to 3.5 to 5.0, but a stabilizer which can satisfy the stability of effective iodine and sucrose is a formulation containing sodium alginate and sodium carboxymethylcellulose (a, b) only.

On the other hand, in the preparations (c, d) to which DL-alanine and sodium caseinate were added, long-term stability was obtained even if the pH immediately after preparation could be in the stable range of sucrose and povidone-iodine. Did not.

[Effects of Stabilizer] In the preparations of the conventional examples, the preparation excluding sodium hydroxide (Comparative Example 1) and the preparation excluding the buffer solution (Comparative Example 2) were treated at 40.degree.
% RH for 10 days.
The stability of H, available iodine and sucrose was examined. In addition, when sodium hydroxide and the buffer were removed, purified water was added instead to make the total amount 100 g. The results and the composition are shown in Table 3 together with the conventional example and the preparation of the present invention (Example 1).

[0042]

[Table 3]

From Table 3, it can be seen that the conventional povidone-iodine preparation cannot satisfy the stability of sucrose unless it contains both sodium hydroxide and a buffer. It can be seen that the stability of sucrose and effective iodine can be satisfied without containing any of sodium hydroxide and a buffer.

[Optimal amount of sodium alginate] As shown in Table 4, Formulation Examples 2 to 5 were the same except for the content of sodium alginate in 100 g of the formulation.
And a preparation containing no sodium alginate (Comparative Example 3). The preparation of Comparative Example 3 became syrupy immediately after preparation.

[0045]

[Table 4]

The preparations of Comparative Example 3 and Examples 2 to 5 were
After preservation at 75 ° C. and 75% RH for 54 days, pH, sucrose, and available iodine were measured immediately after preparation, 10, 30, and 54 days later.

Table 5 shows the measurement results together with those of the conventional example.

[0048]

[Table 5]

As can be seen from Table 5, the preparation containing no buffer, sodium hydroxide, or sodium alginate (Comparative Example 3) had a pH immediately after preparation of 3.5 or less, and was stable in both sucrose and available iodine. Was not obtained.

As the content of sodium alginate increases, the initial pH of the preparation tends to increase, and the sucrose and the sugar of the preparation (Examples 3 to 5) having a sodium alginate content of 1.0 to 2.0% by weight. The stability of effective iodine is about the same, and can be said to be about the same as in the conventional example.

[Necessity of Shape Retaining Agent] A formulation containing sodium alginate and further containing pullulan as a shape keeping agent (Example 7) and a formulation not containing it (Example 6) were prepared. Examples 6 and 7 and the prior art (containing buffer, NaOH, and shape-retaining agent) were left at 40 ° C. and 75% RH for 6 months, and stored at 50 ° C. for 54 days.
The stability of H, sucrose and available iodine was investigated.

The composition and the measurement results are shown in Tables 6 and 7, respectively.

[0053]

[Table 6]

[0054]

[Table 7]

As can be seen from Table 7, the formulation of the present invention was slightly inferior in effective iodine as compared with the conventional example. However, the stability of pH and sucrose was not affected by the presence or absence of the shape-retaining agent. And had stability equal to or higher than the conventional one.

[Differences in Stabilizing Effect Depending on Kinds of Salts] Alginic acid salts such as potassium salts, calcium salts, zinc salts or ammonium salts, and salts of polysaccharide derivatives such as CMC-Na, CMC-Ca, CMS-Na Or a formulation having a composition as shown in Table 8 or Table 9 using croscarmellose-Na as a stabilizer (Examples 8 to 1).
5) was prepared. About the prepared formulation, 40 ° C, 75
It was left for 3 months at% RH, and the pH, sucrose, and stability of available iodine were measured immediately after preparation, 1 month after storage, and 3 months after storage.

Table 8 (Example 8)
11) and Table 9 (Examples 12 to 15).

[0058]

[Table 8]

[0059]

[Table 9]

As can be seen from Table 8, as the salts of alginic acid, potassium salts and ammonium salts showed less change in pH than calcium salts and zinc salts and were excellent in stability of sucrose and effective iodine. Further, as can be seen from Table 9, as the salt of the polysaccharide, the sodium salt showed less change in pH than the calcium salt, and was excellent in the stability of sucrose and effective iodine. In addition, when the properties of the preparation were observed three months later, none of potassium alginate, ammonium alginate, CMC-Na, CMS-Na, and croscarmellose-Na were changed from immediately after,
Calcium alginate and zinc alginate changed to black syrup-like, and CMC-Ca partially changed to syrup-like.

Therefore, it is understood that a monovalent salt has a higher stabilizing effect as a stabilizer.

[0062]

EFFECT OF THE INVENTION The preparation for repairing pressure ulcer / damaged skin of the present invention
The sucrose and effective iodine can be stored stably for a long period of time without adjusting the initial pH of the preparation with a buffer or an alkaline compound, or even without containing a shape-retaining agent. Moreover, the preparation of the present invention is excellent in extensibility at the time of application, and is smooth and excellent in usability.

Further, when alginate is used as a stabilizer, the alginate promotes a hemostatic effect, a granulation regeneration effect, and a repair effect on damaged skin due to a water absorption effect.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 47/36 A61K 47/36 47/38 47/38 (72) Inventor Aki Nishimura 6 Yurinokidai, Mita City, Hyogo Prefecture Kyowa Pharmaceutical Co., Ltd. Research Center (72) Inventor Junya Yamashita 6-7-2 Yurinokidai, Mita City, Hyogo Prefecture Kyowa Pharmaceutical Co., Ltd. Research Center

Claims (5)

[Claims] Claims: 1. A preparation for repairing a decubitus / damaged skin containing 50 to 90% by weight of sugar, 0.5 to 10% by weight of povidone iodine and 1 to 20% by weight of water, wherein lithium and sodium salts of alginic acid are used as stabilizers. A preparation for decubitus / damaged skin repair containing at least one selected from the group consisting of salts, magnesium salts, potassium salts, calcium salts, zinc salts and ammonium salts in an amount of 0.5 to 5.0% by weight. . 2. A preparation for pressure ulcer / damaged skin repair comprising 50 to 90% by weight of sugar, 0.5 to 10% by weight of povidone iodine and 1 to 20% by weight of water, wherein a monovalent salt of alginic acid is used as a stabilizer. From 0.5 to 5.
A preparation for repairing decubitus / damaged skin, comprising 0% by weight. 3. A pressure ulcer / damaged skin repair preparation containing 50 to 90% by weight of sugar, 0.5 to 10% by weight of povidone iodine and 1 to 20% by weight of water, represented by the following formula as a stabilizer: The polysaccharide derivative contains 0.5 to 5.0% by weight of at least one selected from the group consisting of lithium salt, sodium salt, magnesium salt, potassium salt, calcium salt, zinc salt and ammonium salt. Formulation for repairing decubitus and damaged skin. Embedded image (Wherein, R ₁ , R ₂ , and R ₃ may be the same or different, at least one is a carboxymethyl group, the rest is a hydrogen atom, a methyl group, or an ethyl group, and the bond between pyranoses is α-1,4 bond or β-1,4 bond, and n is a natural number) 4. A pressure ulcer / damaged skin repair preparation containing 50 to 90% by weight of sugar, 0.5 to 10% by weight of povidone iodine and 1 to 20% by weight of water, represented by the following formula as a stabilizer: A preparation for repairing decubitus / damaged skin, comprising a monovalent salt of a polysaccharide derivative in an amount of 0.5 to 5.0% by weight. Embedded image (Wherein, R ₁ , R ₂ , and R ₃ may be the same or different, at least one is a carboxymethyl group, the rest is a hydrogen atom, a methyl group, or an ethyl group, and the bond between pyranoses is α-1,4 bond or β-1,4 bond, and n is a natural number) 5. The method according to claim 1, which does not contain a metal hydroxide.
4. The preparation for repairing pressure ulcer / damaged skin according to 4.