WO2004011032A1

WO2004011032A1 - External preparation

Info

Publication number: WO2004011032A1
Application number: PCT/JP2003/009446
Authority: WO
Inventors: Takayuki Ishii; Katsunori Morishita; Tomoaki Takigawa; Toshiaki Sato
Original assignee: Mikasa Seiyaku Co., Ltd.
Priority date: 2002-07-26
Filing date: 2003-07-25
Publication date: 2004-02-05
Also published as: JPWO2004011032A1; JP4712380B2; AU2003252694A1

Abstract

An external preparation comprising a drug component and a wound healing promoter component wherein a hydrophilic polymer such as pectin is employed as the wound healing promoter component to thereby enable effective treatment of a skin disease with a wound.

Description

Specification

External preparation

[Technical field to which the invention belongs]

The present invention relates to an external preparation containing a medicinal ingredient generally known as an external preparation, which also exhibits an effective action of promoting wound healing when applied to a skin disease or the like accompanied by a wound. The present invention relates to an external preparation obtained by blending a wound healing promoting component with an external preparation applied to a part, skin or mucous membrane.

[Conventional technology]

In recent years, skin diseases such as skin ulcers such as pressure ulcers, senile xerosis, atopic dermatitis, etc. in medical institutions and homes have become social problems due to the development of an aging society, changes in lifestyles, and stress. It has increased. In addition, many people are suffering from rough skin, wounds, and scratches due to cracks, rashes, itching, and the like. Conventionally, external preparations have been selected and applied according to each disease. However, when a wound such as a cut is applied to the skin and mucous membrane application site, or when applied to a skin ulcer site such as a pressure sore, there have been cases where some drugs adversely affect wound healing. In addition, skin moisturizing agents, anti-inflammatory agents, anti-allergic agents, local anesthetics, vitamins, and other drugs are used for skin and mucosal diseases associated with wounds, but depending on the disease associated with wounds and mucosal damage. There were also many drugs that would benefit from the inclusion of a wound healing promoter.

Disinfectants and disinfectants are examples of negative effects on wound healing. Disinfectants and disinfectants are widely used for disinfecting and disinfecting wounds, skin and mucous membranes, or for preventing bacterial infection. When these disinfectants are applied to wounds, they show bactericidal and disinfecting effects, but delay wound healing (Kramer S A. J Vase Nurs 17, 17, 23–23, 1 999; E ffectofpovid on e-iocl in eon wo und healing: arevi ew), and disinfectants are known to have an adverse effect on wound healing.

On the other hand, wound healing promoters are used for treatment of pressure ulcers and skin ulcers, etc.If wounds are infected with bacteria, apply the wound healing promoter after disinfecting the wound with a disinfectant / disinfectant There is a need. Wound dressings are also suitable for wounds infected with bacteria. There are also problems such as inapplicability.

Based on these facts, from the viewpoint of wound treatment, it is desirable to use a preparation that simultaneously exerts a bactericidal / disinfecting action and a wound healing promoting action. That is, the combination of a disinfectant and a wound healing promoter is considered to be very useful. However, not all combinations of disinfectants and wound healing promoters are acceptable. It goes without saying that a combination preparation of a bactericidal / disinfectant and a wound healing promoter is stable in terms of formulation, but it must be a formulation that simultaneously exerts bactericidal / disinfecting action and a wound healing promoting action.

Sucrose / povidonodo is used clinically as a formulation containing a disinfectant and a wound healing promoter. However, although bactericidal and disinfecting effects are observed, there are reports that healing is delayed despite the inclusion of sucrose as a component that promotes wound healing. It has not been.

From these facts, there is a demand for the development of a drug that has a bactericidal and disinfecting action and that can heal wounds quickly and accurately.

In addition, preparations containing certain types of wound healing promoters and disinfectants are already known (Japanese Patent Application Laid-Open No. 7-145,081; These are related to ribosome preparations or formulations containing particulate carriers.

On the other hand, urea preparations are an example where it is better to incorporate a wound healing promoter. Urea preparations have been used as an active ingredient for external use on the skin because they have excellent effects on the skin, such as keratin water retention and keratolytic exfoliation. However, it was pointed out that urine is irritating to the skin and mucous membranes and cannot be applied to wounds. From these facts, there is a demand for a drug that can heal wounds quickly and accurately while having a water-retaining effect in the stratum corneum and that can be applied to sites with wounds.

[Object of the invention]

An object of the present invention is to provide an external preparation having an excellent wound healing promoting action and an original pharmacological effect of an external preparation, and capable of efficiently treating a skin disease accompanied by a wound.

[Summary of the Invention] The present inventors have conducted intensive studies to achieve the above object, and as a result, a hydrophilic polymer having a wound healing promoting effect has good compatibility with existing external preparations. The present inventors have found that a wound healing promoting action can be imparted without impairing the medicinal effect, and reached the present invention.

That is, the present invention is an external preparation containing a medicinal component and a wound healing promoting component, wherein the wound healing promoting component comprises a wound healing promoting hydrophilic polymer.

According to the present invention, the wound healing promoting effect and the original pharmacological effect of the external preparation can be sufficiently exhibited only by blending a wound healing promoting hydrophilic polymer with a conventionally used external preparation. It has the advantage of being able to be used in the original mode of use of the agent, and as a result, exhibits great effects in both production and use.

(Preferred embodiment of the invention)

The wound healing-promoting hydrophilic polymer used in the present invention is preferably a polymer that exhibits a wound healing promoting effect of at least 20% in a rat defect wound test, and contains at least one or more of these. The type and structure are not particularly limited as long as it is selected, but preferred wound healing promoting hydrophilic polymers include pectin, alginic acid, carboxymethylcellulose, gum arabic, and pullulan.クチン Kuching, alginic acid and carboxymethylcellulose also include their salts. As pectin which can be used in the present invention, pectin of natural origin, its partial hydrolyzate and physiologically acceptable salts thereof are used. The physiologically acceptable salt is not particularly limited as long as it is physiologically acceptable. The molecular weight of these pectins is from about 30,000 to about 800,000, preferably from about 30,000 to about 750,000, more preferably about 60,000. 0 to about 600,000, particularly preferably about 200,000 to about 500,000. The origin of Pectin is not particularly limited.

The molecular weight means the molecular weight of the main peak measured by gel filtration (TSK-ge LG 400 PW). Pectin has a degree of esterification of 20% or more, preferably 30 to 80%. The ester is preferably a methyl ester, but may be another ester such as a C ₂ -C ₆ alkyl ester.

The carboxymethylcellulose that can be used in the present invention is not particularly limited. Carboxymethylcellulose having a degree of oxidation of 0.4 to 2.0, preferably 0.6 to 1.2, and most preferably 0.65 to 1.0, or a salt thereof is usually used. In addition, the viscosity of the 1% solution is 5 to 3,000 OmPas, preferably 10 to 2, OOOmPas, most preferably 30 to 1,500 mPa's. s is usually used. As alginic acid that can be used in the present invention, alginic acid, its derivatives and physiologically acceptable salts thereof are used. The physiologically acceptable salt is not particularly limited as long as it is physiologically acceptable. Examples of the alginic acid derivative include propylene glycol alginate.

Pharmaceutical ingredients that can be used in the present invention are medically acceptable, and include one or more components that are expected to exhibit a medicinal effect when applied to a wound, skin or mucous membrane, and are classified into those types. Although not limited, typical examples thereof include generally widely used bactericides, disinfectants, skin moisturizers, anti-inflammatory agents, anti-allergic agents, local anesthetics, vitamins and the like.

The germicidal disinfectant that can be used in the present invention is not particularly limited as long as it contains at least one bactericidal / disinfecting agent. Suitable germicidal / disinfecting agents include povidone and podholm, Iodine and iodine complexes such as iodine tincture and resorcinol, benzalkonium chloride, benzethonium chloride, decalinium chloride, cetylpyridinium chloride, cresyl soap, and other disinfecting stone compounds, silver and mercury compounds, erythromycin, gentamicin, Examples include antibiotics such as kanamycin, antifungals, acrinol, chlorhexidine dalconate, and the like.

Examples of the skin moisturizing agent which can be used in the present invention include polyhydric alcohols such as glycerin, propylene glycol, 1,3-butylene glycol, polyethylene glycol, dipropylene glycol, xylitol, sorbitol, free amino acids, urea, Natural moisturizing factors such as lactic acid and citrate, heparin-like substances, collagen, elastin, chondroitin sulfate, dermatan sulfate, fibronectin, hyaluronic acid, ceramide, chitosan, and hydantoin (Japanese Patent Application Laid-Open No. 9-2788645) And the like, but are not limited thereto. These may be used alone or in combination of two or more. Anti-inflammatory agents that can be used in the present invention include, for example, azulene, aminoethyl benzoate, ibuprofen, indomethacin, glycyrrhizic acid, glycyrrhetinic acid, 7-lantoin, copper chlorophyllin, ketoprofen, methyl salicylate, salicylate glycol ester, diclofenac, suprofen, naproxen Non-steroidal anti-inflammatory drugs or their salts, including coX2 selective inhibitors such as piroxicam, felbinac, bufexamac, flurbiprofen, and meloxicam, celecoxib, oral fuecoxib, or salts thereof, alclomethasone, clobesol, Vesuvone, diflucortron, difluprednate, diflorazone, dexamethasone, deprodone, triamcinolone acetonide, halcinonide, hydrocortisone, Zone Nido, fluocinonide, full O rosiglitazone Roh Ron § Seto acetonide, fludroxycortide, flumethasone, prednisolone, beclomethasone, Baie evening methasone, steroids such as mometasone, and the like salts thereof, and the like. These may be used alone or as a mixture of two or more.

Examples of the anti-allergic agent that can be used in the present invention include diphenhydramine, carpinoxamine, dimenhydrinate, diphenirubiralin, clemastine, pyrilamine, triberenamine, chlorpheniramine, triprolysin, dimethindene, promethazine, alimimazine, isothidyl. Antihistamines or their salts, such as hydroxyzine, meclizine, homochlorcyclidine, cyprohepdin, or salts thereof, mexidin, terfenadine, epinastine, astemizole, ebastine, cetirizine, oral ratadine, cromoglycic acid, tranilast, ketotifen, azelastine , Oxatomide, Amlexanox, Repirinast, Ibudilast, Emilo last, Tazanolast, Ozadarrell, Splatast, Seratrodast Emadasu Chin, pranlukast, antiallergics or a salt such as crotamiton, Shikurosu porins, evening Kurorimusu, but we include an immunosuppressant drug or a salt thereof is one bets like methotrexate, but not limited to. These may be used alone or as a mixture of two or more.

Examples of the local anesthetic which can be used in the present invention include, for example, procarin, oxybuprocaine, ethyl amino benzoate, piberidyl acetylaminoethyl benzoate, cocaine, tetracaine, lidocaine, terikin, propitin Power In, Hexochikai , Dimethisoquine, promoxine, benzocaine, benzyl alcohol, catalysin, paletoxicaine, pyro-in, pro-inamide, propara-in, oral oxyn-in, hexylcaine, metabutemin, methtaboxin, pyridoxine, jib Power in, bupipa power in, mepiva power in, oxesazein, and salts thereof, but are not limited thereto. These may be used alone or as a mixture of two or more.

Examples of the vitamin preparations that can be used in the present invention include vitamin A, vitamin B group, bimin (:, vitamin D, vitamin E, vitamin K, vitamin Η, nicotinic acid, pantothenic acid, folic acid, and derivatives thereof, and the like. However, these are not limited thereto, and they may be used alone or in combination of two or more.

The mixing ratio of the two components used in the present invention is selected within a range sufficient to exhibit the respective effects, but the wound healing-promoting hydrophilic polymer is preferably 0.01 to 60% by weight, More preferably, it is used in an amount of 3 to 30% by weight.

The external preparation of the present invention is not particularly limited in other optional components, dosage forms, and the like as long as it contains the above-mentioned components. The external preparation of the present invention exhibits an excellent wound healing promoting effect without impairing the performance as an original external preparation.

Examples of the dosage form of the external preparation of the present invention include semisolid preparations such as ointments, creams, and gels, powder preparations, granules, sticks, sheets (including films), and suppositories. And liquid preparations such as aqueous solutions, suspensions, lotions and emulsions. In addition, these can be used as sprays if necessary. Further, as a patch, a patch, a plaster, a patch and the like can be mentioned, and an ointment, a cream, a gel, a stick, a sheet (including a film), and a cataplasm are preferable.

In addition, the application site of the external preparation of the present invention is not limited by the application range of the existing external preparation such as skin and mucous membrane. That is, depending on the type of existing topical preparation, it can be used for whole body skin and mucous membrane.

In the present invention, if necessary, various components acceptable in the production of pharmaceuticals, that is, aqueous components, oil components, water-soluble polymers, oil-soluble polymers, and oxidized components, as long as the effects of the present invention are not impaired. Inhibitor, surfactant, freshener, buffer, ρΗ A stabilizer, antibacterial and preservative, etc. can be appropriately compounded.

Examples of the aqueous component include lower alcohols such as ethanol, propyl alcohol and isopropyl alcohol; polyhydric alcohols such as glycerin and sorbitol; dalicols such as ethylene glycol, propylene glycol, butylene glycol, and polyethylene glycol; sucrose; Examples include sugars such as lactose, maltose, mannitol, erythritol, and xylitol, sugar alcohols, and purified water.

Examples of the oil component include saturated hydrocarbons such as white petrolatum and liquid paraffin, waxes such as salami beeswax and carnauba wax, oils and fats such as soybean oil and hard fat, stearyl alcohol, oleyl alcohol, and higher alcohols such as cholesterol. Examples thereof include fatty acids such as coals, isopropyl adipate, isopropyl sebacate, octyldodecyl myristate, and cetyl lactate; fatty acids such as palmitic acid, stearic acid, and oleic acid; and silicone oils such as methylpolysiloxane.

Examples of the water-soluble polymers include plant polymers such as guar gum, karaya gum, carrageenan, agar, starch, tragacanth gum, and oral cast bean gum; microbial polymers such as xansu gum, dextran, collagen, casein, and gelatin. Alginic acid polymers such as methylcellulose, methylcellulose, methylhydroxypropylcellulose, nitrocellulose, sodium cellulose sulfate, cellulosic polymers such as crystal cell mouth, polyvinyl methyl ether, Polymer, polyoxyethylene-based polymer, polyacrylic acid-based polymer, polyvinyl alcohol, polyvinylpyrrolidone, and the like.

Examples of the oil-soluble polymer include an acrylic acid / alkyl methacrylate copolymer.

Examples of the surfactant include sorbitan monolaurate, sorbitan sesquioleate, sorbitan trioleate, polyoxyethylene sorbitan monolaurate, polyethylene glycol monoolate, polyoxyethylene alkyl ester, polyglycol ester, and lauroyl ester Evening amide, fatty acid isopropanolamide, maltitol hydroxyaliphatic ether, alkylated poly Nonionic surfactants such as sugars, alkyl darcosides, sugar esters, etc., cationic surfactants such as stearyl trimethylammonium chloride, lauryl amine oxide, sodium palmitate, sodium laurate, potassium lauryl sulfate, alkyl Examples thereof include anionic surfactants such as triethanolamine sulfate, linear dodecylbenzene sulfate, polyoxyethylene hydrogenated castor oil, maleic acid, and acylmethyltaurine, and naturally-derived surfactants such as lecithin and derivatives thereof.

Examples of the antioxidant include tocopherol, ascorbic acid, erythorbic acid, propyl gallate, BHT (dibutylhydroxytoluene), and BHA (butylhydroxyanisole).

Examples of the cooling agent include menthol and camphor.

As the buffer, for example, disodium hydrogen phosphate-monocitrate, dihydrogen phosphate-disodium hydrogen phosphate, disodium citrate-disodium hydrogen phosphate and the like can be mentioned.

Examples of the pH regulator include organic acids such as citric acid, acetic acid, malic acid, lactic acid, and tartaric acid, and metal salts thereof, amine salts such as monoethanolamine, jetanolamine, and triethanolamine, phosphoric acid, Inorganic acids such as boric acid and hydrochloric acid; metal salts thereof; hydroxide salts such as sodium hydroxide and potassium hydroxide; and carbonate salts such as sodium carbonate.

Antibacterial and preservatives include, for example, benzoate, salicylate, sorbate, dehydroacetate, paraoxybenzoate, 2,4,4'-trichloro-2'-hydroxydiphenyl ether, benzalkonium chloride , Ethanol and the like.

〔Example〕

Next, the present invention will be described in more detail by way of examples to illustrate the present invention, but the present invention is not limited to the examples.

Example 1: Rat defect wound test

Five-week-old male male Wistar rats were preliminarily reared for one week before being subjected to the test. After shaving the back of the rat with an electric clipper, the back was removed under pentoparbital anesthesia. It was punched with a circular punch of 10 mm in diameter, and two punched wounds symmetrical about the median line were created. The size of the wound surface (major axis X minor axis) immediately after punching was measured with a caliper. The test preparation was applied to each defect at a dose of 100 mg once a day from the wound wound creation date to the test end date, covered with a cloth and film, and then fixed with adhesive tape.

From 4 days after the creation of the defective wound to the 15th day, the major axis and minor axis of the non-epithelialized wound area were measured to determine the area, and the area change curve of the wound area was calculated by the following formula to create an area change curve. . Wound area on each measurement day

Area change = = X 1 0 0

Wound area on the day of defect wound creation The area under the area change curve was calculated, and the effect of promoting wound healing was calculated by the following formula, and used as an index of the effect of promoting wound healing. (The larger the value, the stronger the wound healing promoting effect.) The area under the curve of each test preparation-administered animal

Wound healing promoting effect (%) X 100

Average value of the area under the curve in the control group The test drug prepared using Macrogol as a base and the isodine (comparison drug)

Table 1 shows the results of the gel (Meiji Seika Co., Ltd.). As is evident from the results, the combination of ぺ -kutin and povidonodo (Formulation No. 4) showed a clearly stronger wound healing promoting effect than the povidone-doped formulation (Formulation No. 2) or the comparative drug. The pectin used in these cases was a pectin having a molecular weight of about 300,000 and a degree of (methyl) esterification of 74%, unless otherwise specified. NNN

o〇 o 10

table 1

Wound healing promotion effect

Formulation name

(%)

Comparative drug Isodine ™ gel 1 1.1 ± 4.1

No. 1 base (macrogol) 0.7 ± 1.7

No. 2 Povidone (10% by weight) 9.1 ± 7.6

No. 3 Pectin (10% by weight) 60.2 ± 1.2

No. 4 Pectin (10% by weight) + povidone 54.4 ± 2.4

Eodo (10% by weight)

The test drug was prepared based on macrogol.

A negative value for the wound healing promoting effect indicates that healing is delayed compared to the control.

Table 2 shows the results of the test drug prepared by dissolving (suspending) in water and Isodin (trademark) liquid (Meiji Seika Co., Ltd.), which is a comparative drug. As is evident from the results, the combination of Pectin and Povidonide (Formulation No. 8) showed a clearly stronger wound healing promoting effect than the Povidonold formulation (Formulation No. 6) or the comparative drug.

Table 2

Wound healing promotion effect

Formulation name

(%)

Comparative agent (trademark) liquid

No. 5 Water 1 7 ± 3 4

6 Povidondo (10 weight:;%) 9 7 ± 4 3

7 Pectin (10% by weight) 46 7 ± 50

8 Pectin (10% by weight) + povidone 43 1 ± 4 5

(10% by weight)

The test drug was prepared by dissolving (suspending) it in water.

Table 3 shows the results of the test drug prepared using white petrolatum as a base and the comparative drug Elis Mouth Shin ™ Ointment (Dainippon Pharmaceutical Co., Ltd.). Erythromycin formulation (Formulation No. 10) 'and the comparative drug delayed wound healing. In contrast, a combination of Pectin and erythromycin (Formulation No. 12) clearly showed a strong wound healing promoting effect. Table 3

Wound healing promotion effect

Formulation number Formulation name

(%)

Comparative drug Elis Mouth Shin ™ Ointment 29.8 ± 12.7 No. 9 base (white petrolatum) 4.8 ± 3.3

No. 10 Erythromycin (1% by weight) 37.7 ± 5.0

No. 11 Pectin (10% by weight) 58.3 ± 5.5

No. 12 Pectin (10% by weight) + Ellis 37.9 ± 1.9

Lomycin (1% by weight)

The test drug was prepared based on white petrolatum.

Table 4 shows the results of the test drug and the comparative drug Hibitene (trademark) gel (Sumitomo Pharmaceutical Co., Ltd. · AstraZeneca Co., Ltd.), which were prepared using the 〇 / W emulsion base. Chlorhexidine gluconate (Formulation No. 14) and a comparative drug delayed wound healing. In contrast, a combination of pectin and chlorhexidine dalconate (Formulation No. 16) clearly showed a strong wound healing promoting effect.

Table 4

Wound healing promotion effect

Formulation name

()

Comparative drug Hibiten ™ gel-55.9 Sat 2.9

No. 13 base (〇 \\ type emulsion base) 10.1 ± 4.2

No. 1 Chlorhexidine dalconate (single-14.2 ± 8.5

No. 15 Pectin (10% by weight) 590 ± 4.8

No. 16 Pectin (10% by weight) + Dalcon 260 ± 2.4

(1% by weight)

The test drug was prepared based on an O-type emulsion base.

Table 5 shows the results of the test drugs prepared based on white P-serine. As is evident from the results, even with the combination of sodium alginate, carboxymethylcellulose mono-Na or pullulan and povidonodo (formulation no. It showed a healing promoting effect. NNNNNN

o o o o o o 12 Table 5

Wound healing promotion effect

Formulation number Formulation name

(%)

17 (white serine) 4. 9 ± 19

18 Povidon (10 times;%) 5.8 ± 5 5

19 'Acid Na (10 fold:%) 35.3 ± 8 1

20 'acid Na (10-fold j;%) + 33.4 ± 6 3

Povidonold (10th j;)

No. 21-S Na 43.5 ± 2

(10% by weight)

No. 22 source Na 41.0 ± 3

(10% by weight) + Povidone

(10% by weight)

23 (10% by weight) 22 5 ± 1 9

24 (10% by weight) + povid 28 0 ± 4 6

Nyodo (10% by weight)

The test drug was prepared based on a 0 ZW type emulsion base.

From the above results, it was clarified that a preparation comprising a wound healing-promoting hydrophilic polymer and a bactericidal / disinfectant exhibited a wound healing promoting effect.

Example 2: Bactericidal test

S taphylococcusepide rm idis cell suspension (10 ⁶ cells / mL) Add 4.5 g or 4.5 mL of each test preparation to 10 OmL, and immediately shake at 37 ° C and 100 rpm to obtain the sample solution. And After 10 minutes and 20 minutes from the start of shaking, 0.2 mL of 0.1 mo 17L thiosulfate Na solution was added to inactivate povidone, and the cells were cultured at 37 ° C for 48 hours. As a control, 4.5 mL of sterilized physiological saline was added to 10 OmL of a 10 ⁶ cells // mL bacterial suspension, and the test was carried out in the same manner as for each preparation.

When the medium became turbid after 48 hours, the growth of Staphylococ c cusep epidermidis was recognized, and it was determined that there was no bactericidal effect. In addition, when the medium was transparent without turbidity, the growth of Staphylococ cucepidermidis was not recognized, and it was determined to have "bactericidal effect".

Isodine ™ gel (Meiji Seika Co., Ltd.) and Isodine ™ liquid (Meiji Seika Co., Ltd.), which are comparative drugs, exhibited antibacterial activity. On the other hand, antibacterial activity was also observed with the combination of Pectin and Povidonol (Formulation Nos. 4 and 25). This And showed antibacterial activity even when mixed with Pectin.

Table 6

Formulation number Formulation name Antibacterial activity

Control mouth saline

Comparative Drug ™ gel +

Comparative drug (trademark) liquid +

No. 3 Pectin 10 weight ”% ointment (Macrogo

Base)

No. 4 Pectin 10 weight ”% + Povidoncho +

De 10th layer:% ointment (Macrogol group

Agent)

No. 15 Pectin 0% by weight (OZW emulsion

Base)

No. 25 Pectin 0% by weight + Povidon +

C, 1 (OZW emulsion base)

1. No antibacterial activity + antibacterial activity

From the above results, it was clarified that a preparation comprising a wound healing promoting hydrophilic polymer and a disinfectant / disinfectant exhibited a disinfecting / disinfecting action, and had both a disinfecting action and a wound healing promoting action.

Example 3: Examining the molecular weight of Pectin and its effect on promoting wound healing

Table 7

Wound healing promoting effect Formulation name molecule j

()

No. 26 Pectin (10% by weight) About 300,000 52. 8 ± 3.2

No. 27 Pectin partial hydrolyzate A (10 about 200,000 37.2 ± 4.7% by weight)

No. 28 Pectin partial hydrolyzate B (10 about 60,000 27.1 ± 7.7% by weight)

No. 29 Pectin partial hydrolyzate C (10 about 30,000 22.0 ± 5.8% by weight)

No. 30 Pectin partial hydrolyzate D (10 about 3,000 20.1 ± 3.8% by weight) ____ The test drug was prepared based on plastibase.

The molecular weight indicates the molecular weight of the main peak measured by gel filtration.

A partial hydrolyzate of pectin was prepared by treating pectin (molecular weight about 300,000, esterification degree 74%) with pectinase. The molecular weight is T

Measure the main peak by gel filtration with SK-gel G4000 PW. Four

The molecular weight of the main peak was determined using a standard sample (Standard P-82, Showa Denko).

Wound healing promoting action was observed from a peak molecular weight of about 3,000 to about 300,000. As the peak molecular weight increased, the wound healing promoting effect became stronger, and a peak molecular weight of 200,000 or more ( Formulation Nos. 26 and 27) were found to have a strong wound healing promoting effect.

Example 4: Examination of the degree of esterification of pectin and the effect of promoting wound healing

Table 8

Wound healing promoting effect Formulation name Esterification degree

(%)

No. 31 Pectin A (10% by weight) 74% 52.8 ± 3.2

No. 32 Pectin B (10% by weight) 36% 5 1.1 ± 3.1

No. 33 Pectin C (10% by weight) 3 1% 49.0 ± 3.1

No. 34 Pectic acid (10% by weight) 0% 7.0 ± 3.5 Test drugs were prepared based on plastibase.

The molecular weights of Pectin A are about 300,000, and that of Pectin B and Vectin C are about 250,000. Table 8 shows the results of the wound healing promoting effect of pectins having different degrees of esterification. Vectin with a degree of esterification of 31 to 74% exhibited a wound healing promoting effect. On the other hand, no effect of promoting wound healing was observed with pectic acid having a degree of esterification of 0%.

Example 5: Guinea pig rough skin improvement test

A rough skin model was prepared according to the method of Sagi V et al. (Skin Res Tecno 6; 372000). However, for the purpose of the present invention, it was necessary to prepare a more severe rough skin model, so that the concentration of the surfactant for causing rough skin, i.e., sodium lauryl sulfate, was increased, and the Hartley guinea pig was used as a severe rough skin model. After shaving the back coat, a 2.5 cm X 2.5 cm cloth immersed in 5% aqueous sodium lauryl sulfate solution was applied once a day for 5 minutes for 3 consecutive days. Skin roughness was produced. Two days after the final application, the transdermal water loss (TEWL) of the rough skin was measured, and then the test drug was applied on each side at 10 Omg. After 24 hours, the TEWL was measured again. Arithmetic (The larger the value, the stronger the effect of promoting the improvement of skin roughness.) The uncoated area was taken as the control area.ヽ

Average value of each test drug administration group

Skin roughness improvement promotion effect (%) X 100

Average value of control group No. A skin external ointment having the composition shown in Table 9 was prepared in a mortar using white ヮ -serine as a base, and the effects of promoting wound healing and improving skin roughness were examined. Unless otherwise specified, the blending amount is shown in% by weight. As a result, the preparations containing Pectin (Formulation Nos. 35 and 36) showed an extremely high wound healing promoting effect as compared with Comparative Preparations 1 and 2 containing no Pectin. A preparation containing urea (Formulation No. 35, Comparative Preparation 2) was found to have an effect of improving skin roughness. That is, it was clarified that the preparation containing urea and pectin (formulation No. 35) had an effect of promoting wound healing and an effect of improving skin roughness.

Table 9

Skin external ointments having the composition shown in Table 10 were prepared, and the effects of promoting wound healing and improving skin roughness were examined. The amounts are by weight unless otherwise specified. as a result

On the other hand, the preparation containing Pectin (Formulation Nos. 37 and 38) showed an extremely high wound healing promoting effect as compared with Comparative Preparations 3 and 4 containing no Pectin. In addition, the preparations containing urea (Formulation No. 37, Comparative Preparation 4) were found to have an effect of improving skin roughness. In other words, it was revealed that a preparation containing urea and pectin (Formulation No. 37) had an effect of promoting wound healing and improving skin roughness. Table 10

Skin external ointments having the composition shown in Table 11 were prepared, and the effects of promoting wound healing and improving skin roughness were examined. The amounts are by weight unless otherwise specified. as a result

On the other hand, the preparations containing Pectin (Formulation Nos. 39 and 40) showed an extremely high wound healing promoting effect as compared with the comparative preparations 5 and 6 containing no Pectin. Formulations containing urea (Formulation No. 39, Comparative Formulation 6) were found to have an effect of improving skin roughness. In other words, it was revealed that a preparation containing urea and pectin (formulation No. 39) had an effect of promoting wound healing and an effect of improving skin roughness.

Table 11

From the above results, it is clear that a formulation containing Vectin, a hydrophilic polymer that promotes wound healing, and urea, which has a skin moisturizing effect, can be used with any base, even if urea has a skin moisturizing effect and a wound healing promoting hydrophilicity. Since the effect of promoting the wound healing was exhibited by the conductive polymer, it was suggested that the present invention was very useful.

Claims

The scope of the claims

1. An external preparation characterized by compounding a medicinal ingredient with a wound healing promoting hydrophilic polymer as an active ingredient.

2. The external preparation according to claim 1, wherein the wound healing-promoting hydrophilic polymer is a hydrophilic polymer that exhibits a wound healing promoting effect of 20% or more in a rat defect wound test.

3. The external use according to claim 1 or 2, wherein the wound healing promoting hydrophilic polymer is at least one kind or two or more kinds selected from the group consisting of pectin, alginic acid, carboxymethyl cellulose, gum arabic and pullulan. Agent.

4. The external preparation according to any one of claims 1 to 3, wherein the medicinal component is a medicinal component that exerts an effect when applied to a wound site, skin, mucous membrane, or damaged mucosa.

5. The medicinal component is at least one or more selected from the group consisting of a bactericidal / disinfectant, a skin moisturizer, an anti-inflammatory agent, an anti-allergic agent, a local anesthetic and a pinumin agent. An external preparation according to any one of claims 1 to 4.

6. The external preparation according to any one of claims 1 to 5, wherein the medicinal component is a disinfectant.

7. The external preparation according to claim 6, wherein the disinfectant / disinfectant is iodine and an iodine complex.

8. The external preparation according to claim 7, wherein the iodine and iodine complex is povidone oxide.

9. The disinfectant according to claim 6, wherein the disinfectant is an antibiotic.

10. The external preparation according to claim 6, wherein the disinfectant is a fungicide.

7. The external preparation according to claim 6, wherein the disinfectant is a disinfecting stone compound.

12. The external preparation according to claim 6, wherein the disinfectant / disinfectant is a phenolic compound.

1 3. The external preparation according to claim 6, wherein the disinfectant is chlorhexidine dalconate.

14. The external preparation according to claim 6, wherein the sterilizing / disinfecting agent is acrinol.

1 5. The external preparation according to any one of claims 1 to 5, wherein the medicinal component is a skin moisturizer.

16. The external preparation according to claim 15, wherein the skin moisturizing agent is a natural moisturizing factor.

1 7. The external preparation according to any one of claims 1 to 5, wherein the medicinal component is an anti-inflammatory agent.

1 8. The external preparation according to any one of claims 1 to 5, wherein the medicinal component is an antiallergic agent.

1 9. The external preparation according to any one of claims 1 to 5, wherein the pharmaceutically active ingredient is a local anesthetic.

20. The external preparation according to any one of claims 1 to 5, wherein the medicinal ingredient is a vitamin preparation.

21. The external preparation according to any one of claims 1 to 20, wherein the wound healing promoting hydrophilic polymer is pectin.

22. The external preparation according to claim 21, wherein the molecular weight of Pectin is about 3,000 to about 800,000.

23. The external preparation according to claim 21 or 22, wherein the molecular weight of Pectin is about 200,000 to about 500,000.

24. The external preparation according to any one of claims 21 to 23, wherein the degree of esterification of pectin is 20% or more.

25. The external preparation according to any one of claims 21 to 24, wherein the degree of esterification of pectin is 30 to 80%.

26. The external preparation according to any one of claims 1 to 20, wherein the wound healing-promoting hydrophilic polymer is alginic acid.

27. The external preparation according to any one of claims 1 to 20, wherein the wound healing-promoting hydrophilic polymer is carboxymethylcellulose.

28. The external preparation according to any one of claims 1 to 20, wherein the wound healing promoting hydrophilic polymer is gum arabic.

29. The external preparation according to any one of claims 1 to 20, wherein the wound healing promoting hydrophilic polymer is pullulan.

30. The external preparation according to any one of claims 1 to 29, wherein the dosage form is a solid preparation.

3 1. The external preparation according to any one of claims 1 to 29, wherein the dosage form is a semi-solid preparation.

32. The external preparation according to any one of claims 1 to 29, wherein the dosage form is a liquid preparation or an aerosol preparation.

33. The external preparation according to any one of claims 1 to 29, wherein the dosage form is a patch.

34. The external preparation according to any one of claims 1 to 33, wherein the content of the wound healing-promoting hydrophilic polymer is 0.01 to 60% by weight.

35. The external preparation according to any one of claims 1 to 34, wherein the content of the wound healing promoting hydrophilic polymer is 3 to 30% by weight.