JP2004262772A - Glycyrrhizin-containing percutaneous pharmaceutical preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a percutaneous pharmaceutical preparation effective for therapy and/or prophylaxis of skin diseases such as a bruise, a burn or a bedsore. <P>SOLUTION: The percutaneous pharmaceutical preparation is composed of an aqueous solution containing glycyrrhizin as an active ingredient. The percutaneous pharmaceutical preparation is an aqueous solution containing aqueous ammonia. <P>COPYRIGHT: (C)2004,JPO&NCIPI

Description

[0001]
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a glycyrrhizin-containing transdermal formulation, and more particularly, the present invention relates to a glycyrrhizin-containing transdermal formulation that is effective for treating bruises, burns or pressure sores.
[0002]
[Prior art]
Glycyrrhizin, a main component of licorice, is a conjugate of glycyrrhetin and two molecules of glucuronic acid. Glycyrrhizic acid and its salts (eg, dipotassium glycyrrhizinate, tripotassium glycyrrhizinate, disodium glycyrrhizinate, trisodium glycyrrhizinate, monoammonium glycyrrhizinate, diammonium glycyrrhizinate, etc.) are used as sweeteners. Glycyrrhizin also has an anti-inflammatory effect (Inoue, H., et al., Chemi. Pharm. Bull., 35 , 3883-3889, 1987; and Inoue, H., et al., Chem. Pharm. Bull., 34 . , 897-901, 1986), and enhances the innate immunity of the living body (Hiroshi Seino: Innate immunity in mucosal immunity, Molecular Medicine, 36 (5), 520-526, 1999; and Katsuo Kumagai: Overview, bacteria in innate immunity). Single copy: Inflammation and immunity, September 2001), which has the ability to enhance the ability of substances to pass through mucous membranes and skin (Motohiro Mishima et al., Biol. Pharma. Bull, 18 (4) 566). -570, 1995; and Wang, Z., et al., Bio. .Pharm.Bull., 17, (10) 1389-1403, 1994) it is known.
[0003]
Skin disorders (eg, burns, wounds, general surgical wounds, erythema, bedsores, folliculitis, impetigo, intertrigo, radiation ulcers, acne vulgaris or eczema-like infectious dermatitis) Erythema, swelling, blisters, erosions, or ulcers, often accompanied by bacterial infection. For the purpose of treating these skin diseases, topical preparations containing an activator of tissue regeneration and an antibiotic capable of promoting the regeneration of necrotic tissue and the proliferation of fibroblasts have been developed. However, these preparations often fail to provide a sufficient therapeutic effect.
[0004]
For example, when a patient becomes bedridden, bedsores (pressure sores) are more likely to occur, and its prevention and treatment have been difficult. Conventionally, treatment of pressure ulcers in such patients includes treatment with physiological saline, disinfectant, and sonar paste (isodin sugar ointment, disinfectant). And Actosin ointment (an ointment that promotes the therapeutic effect of pressure ulcers, a drug that promotes granulation) and the like. For patients who did not benefit from these treatments, they used existing ointments and dressings to treat pressure ulcers. However, these methods may not provide a sufficient therapeutic effect. In addition, there have been reports of cases of treating pressure sores by intravenous injection of glycyrrhizin (Yoshio Nakamizo et al., Effect of glycyrrhizin preparation on treatment of sores, Clinical and Research, Vol. 72, No. 6, 231-234, 1995), there has been no report on treating pressure sores by transdermal administration of glycyrrhizin.
[0005]
[Non-patent document 1]
Inoue, H .; , Et al., Chemi. Pharm. Bull. , 35 , 3883-3889, 1987.
[Non-patent document 2]
Inoue, H .; Chem. Pharm. Bull. , 34 , 897-901, 1986.
[Non-Patent Document 3]
Hiroshi Kiyono: Innate Immunity in Mucosal Immunity, Molecular Medicine, 36 (5), 520-526, 1999
[Non-patent document 4]
Katsuo Kumagai: Overview, Bacterial recognition mechanism in innate immunity. Single manuscript: Inflammation and immunity, September 2001 [Non-Patent Document 5]
Motohiro Mishima et al., Biol. Pharma. Bull, 18 (4) 566-570, 1995.
[Non-Patent Document 6]
Wang, Z .; Biol. Pharm. Bull. , 17, (10) 1384-1403, 1994.
[Non-Patent Document 7]
Yoshio Nakamizo et al., Effect of glycyrrhizin preparation on treatment of pressure sore wounds, Clinical and research, Vol. 72, No. 6, 231-234, 1995
[0006]
[Problems to be solved by the invention]
An object of the present invention is to solve the above-mentioned problems of the conventional technology. That is, an object of the present invention is to provide a transdermal preparation which is effective for treating and / or sometimes preventing skin diseases such as bruises, burns or pressure sores.
[0007]
[Means for Solving the Problems]
The present inventors have conducted intensive studies to solve the above problems, and as a result, spraying and applying an aqueous solution containing glycyrrhizin as an active ingredient to the trunk of a patient suffering from bruises, burns or pressure sores, has reduced these symptoms. They have found that they can be relaxed, and have completed the present invention.
[0008]
That is, according to the present invention, there is provided a transdermal preparation comprising an aqueous solution containing glycyrrhizin as an active ingredient.
Preferably, the aqueous solution is an aqueous solution containing ammonium water.
Preferably, the aqueous solution is a hydrophobically converted aqueous solution containing a solvent.
Preferably, the solvents are glycerin and ethanol.
[0009]
Preferably, the concentration of glycyrrhizin in the aqueous solution is from 0.01 to 5% by weight.
Preferably, glycyrrhizin is obtained by purifying licorice extract by HPLC.
Preferably, the transdermal formulation of the invention can be used for the treatment and / or prevention of bruises, burns or pressure sores.
[0010]
According to another aspect of the present invention, a transdermal preparation comprising an aqueous solution containing glycyrrhizin as an active ingredient is transdermally administered to the skin, for treating and / or preventing bruises, burns or pressure sores. A method is provided.
[0011]
BEST MODE FOR CARRYING OUT THE INVENTION
Hereinafter, embodiments of the present invention will be described.
The transdermal preparation of the present invention is characterized by comprising an aqueous solution containing glycyrrhizin as an active ingredient.
Glycyrrhizin used in the present invention can be obtained, for example, by purifying licorice extract by HPLC (National Institute of Health Sciences, Glycyrrhizic Acid Standard (Control 991). Hiroyuki Saito et al., Bull. Natl. Sci. 117, 195-198, 1999). Specifically, glycyrrhizic acid and salts thereof (eg, dipotassium glycyrrhizinate, tripotassium glycyrrhizinate, disodium glycyrrhizinate, trisodium glycyrrhizinate, monoammonium glycyrrhizinate, diammonium glycyrrhizinate, etc.) can be used. it can.
[0012]
The concentration of glycyrrhizin in the aqueous solution is not particularly limited as long as the desired drug effect can be achieved, but is generally 0.01 to 5% by weight, preferably 0.05 to 1% by weight. It is difficult to sufficiently exert the medicinal effects of glycyrrhizin, which is an active ingredient. On the other hand, if the concentration is too high, it is difficult to achieve an effect that is commensurate with an increase in the amount of the compound.
[0013]
The water used for preparing the transdermal formulation of the present invention may be any water used in the field of ordinary pharmaceuticals, and is not particularly limited.
Water can be added in the remaining amount of the total amount of other essential components and optional components contained in the transdermal formulation of the present invention. In the present invention, it is preferably about 70 to 99% by weight, particularly about 75 to 99% by weight.
[0014]
Preferably, a small amount of aqueous ammonium can be added to the transdermal formulation of the present invention for solubilizing glycyrrhizin in water. The amount of ammonium water added may be such that glycyrrhizin can be solubilized in water, and is generally about 0 to 1.0% by weight based on the total amount of the aqueous solution.
[0015]
More preferably, in the transdermal formulation of the present invention, a solvent can be added to the aqueous glycyrrhizin solution to convert the aqueous glycyrrhizin solution to hydrophobic in order to enhance the skin permeability of the glycyrrhizin aqueous solution. As the solvent used herein, alcohols can be used. Specifically, polyhydric alcohols such as glycerin and monohydric lower alcohols (for example, methanol, ethanol, normal propanol, isopropanol, normal butanol, t-butyl alcohol) Etc.) can be used. These may be used alone or as a mixture of two or more. Preferably, glycerin and ethanol can be used in combination. The content of the solvent such as alcohol (the total content when two or more alcohols are used) is not particularly limited, but is preferably about 1 to 30% by weight, and particularly preferably about 10 to 30% by weight. It is. As an example, glycerin and ethanol can be added in an amount of 19.3% by weight and 6.1% by weight, respectively, based on an aqueous glycyrrhizin solution.
[0016]
The skin external preparation of the present invention includes a pH buffering agent, a surfactant, a saccharide, a solubilizing agent, a chelating agent, a preservative, which are usually added in the formulation, in addition to the above components, as long as the effects of the present invention are not hindered. Additives such as a cooling agent, a thickening agent or a gelling agent can be blended.
[0017]
Specifically, examples of the pH buffer include boric acid, sodium hydrogen phosphate, glacial acetic acid, citric acid, sodium hydroxide, triethanolamine, ascorbic acid, glycine, L-arginine, benzoic acid, sodium benzoate, Sodium chloride, glucose and the like can be used.
[0018]
As a surfactant, polyoxyethylene hydrogenated castor oil 60, self-emulsifying glyceryl monostearate, or the like can be used. As a saccharide, mannitol or the like can be used, and as a solubilizing agent, β- Cyclodextrins such as cyclodextrin, propylene glycol and the like can be used, and sodium edetate and the like can be used as a chelating agent.
[0019]
Also, ethanol, benzalkonium chloride, sorbic acid and the like can be used as a preservative, d-camphor, cauliflower oil, l-menthol and the like can be used as a refreshing agent, and a thickener or As a gelling agent, carboxyvinyl polymer, glycerin monooleate, or the like can be used.
[0020]
Here, the external preparation for skin of the present invention is not particularly limited in its dosage form, and can be prepared as an oily preparation, an emulsion preparation, an aerosol preparation, or the like, but is preferably prepared as an aqueous preparation. It is effective to prepare it as a gel, lotion, poultice, etc.
[0021]
In order to produce the transdermal preparation of the present invention using the above-mentioned essential components and optional components, a conventional method may be used.For example, these components are weighed, and if necessary, heated and stirred to obtain water. The transdermal preparation of the present invention can be produced by dissolving the same in a solution and cooling.
[0022]
The dosage form of the transdermal formulation of the present invention is not particularly limited as long as it is a form suitable for transdermal administration, and can be formulated into any form. The transdermal formulation of the present invention can be prepared into, for example, sprays, gels, lotions, cataplasms and the like, and the preparation method can be prepared by a conventional method of each formulation.
[0023]
Specifically, if it is a propellant, it can be prepared in an aerosol form such as a spray by combining with a propellant. Examples of the propellant include Freon gas such as Freon 11, Freon 12, Freon 21, Freon 113, Freon 114 or Freon 134a, hydrocarbon-based gas such as propane, butane, isobutane, normal butane, isopentane or normal pentane, and dimethyl ether. Liquefied gas, carbon dioxide gas, nitrogen gas or the like can be used.
[0024]
In the case of a gel agent, for example, glycyrrhizin and other optional components are sequentially added to and dissolved in purified water, and each component is adjusted to a desired concentration by further adding purified water to the obtained solution, and optionally, a pH buffer. After finally adjusting the pH of the preparation to a desired pH with the agent, a gelling agent can be obtained by adding a gelling agent to cause gelation.
[0025]
In the case of a lotion, for example, glycyrrhizin and other optional components are sequentially added and dissolved in purified water, and further purified water is added to the obtained solution to adjust each component to a desired concentration, and if necessary, pH buffer. A lotion can be obtained by finally adjusting the pH of the preparation to a desired pH with the agent.
[0026]
If it is a poultice, for example, glycyrrhizin, and other optional components are sequentially added to purified water, dissolved, kneaded for an appropriate period of time, and after final adjustment of the pH as necessary, a nonwoven fabric or the like using a spreading machine or the like. After spreading the support so as to have a constant thickness, covering the surface with a plastic film or the like as necessary, a method of obtaining a poultice by cutting the film to an appropriate size as necessary can be mentioned. .
[0027]
The amount and usage of the transdermal preparation of the present invention are not particularly limited, and may be appropriately set depending on various factors including conditions such as the type and severity of the disease, the dosage form, and the age and weight of the patient. it can. Generally, the dose of glycyrrhizin as an active ingredient is about 10 to 50 μg / kg per day, and preferably about 10 to 20 μg / kg per day. It is preferable to administer the above dose of the drug in about 1 to 4 times a day.
[0028]
The transdermal formulation of the present invention can be used, for example, for the treatment and / or prevention of bruises, burns or pressure sores, and furthermore, bites caused by snakes (particularly when the type of snake is unknown and antiserum cannot be selected). , As well as for treating bee stings.
The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to the examples.
[0029]
【Example】
Glycyrrhizin (GL) water used in the following examples was prepared as follows.
(How to make 0.2% GL water)
To 40 mg of glycyrrhizin, add 19 ml of purified water + 930 μl and 70 μl of 2.8% ammonium, and mix well until completely dissolved.
[0030]
Example 1: A case in which a bruise was treated with glycyrrhizin (GL) water Everyone suffers a light bruise or a minor burn in daily life while spraying GL water, Activates the anti-inflammatory effect and shows a therapeutic effect.
A 77-year-old male patient who had bruised the back of his right hand (at the phalanx of the second finger) showed severe pain and swelling, with visible swelling and subcutaneous bleeding on the back of his hand. Four minutes after the injury, GL water was sprayed onto the wound as a treatment, and spraying and subsequent application were repeated every 4 to 5 minutes. That is, GL water sprayed on the affected part surface with the left finger was spread and applied on the surface of the affected part. After 30 minutes, the swelling had almost disappeared and the pain was completely healed.
[0031]
Since this trial was a condition that could be reproduced with a healthy person as a control, a control experiment was performed with the consent of the patient using the contralateral left hand. Although the symptoms were lighter than the previous time, similar bruises could be made. A PBS solution (buffer solution) was sprayed and applied as a control drug instead of administration of GL water. The pain and swelling of the control did not disappear at all in a short time of 30 minutes, and the inflammatory symptoms continued after 2 days, and were almost cured on the 5th day, with a trace of subcutaneous hemorrhage.
[0032]
In the comparison between the GL water group and the PBS group as a control, the time required for the GL group to be completely cured was 35 minutes, whereas the control group was 120 hours, and the difference was clear. That is, GL water was proved to be effective for bruises.
Unlike the cooling method after bruising used in various sports, it is considered that the anti-inflammatory effect and the pain-relieving effect of GL function under a physiological environment under normal body temperature. GL Water is also expected to be a good painkiller that does not leave any aftereffects in the sports world.
[0033]
Example 2: Example of healing a second-degree burn (burn blister) with GL water Similar to the above-mentioned bruise, a small burn (light burn like erythema) is sprayed and applied two to three times with GL water. Healed easily. Apart from these mild cases, burns accompanied by blisters were completely cured by the spray application of GL and the blisters were reduced. The three burns are described below.
[0034]
(1) A man (77 years old) accidentally poured hot water between the second and third left fingers.
Immediately after the injury, the injured hand was immersed in water and cooled, but erythema appeared at the injured area within 1 to 2 minutes, inflammation started, and the symptoms progressed. So I took my hand out of the water, wiped it off, and continued observation. Subsequently, relatively large red bean bubbles appeared on the first finger and the far second finger side. At this point, spraying and application of GL water to the injured skin (immediately above the blisters) were started (4 minutes after the injuries). Then, after only one minute, the growth of water bubbles stopped, and the water bubbles reversed and started to shrink. The blisters disappeared in just one minute and turned into erythema in the next less than a minute. All inflammatory lesions disappeared visually within 10 minutes after administration of the GL water. On the next day, erythema again and faintly appeared in the blister part yesterday, but the lesion disappeared by the second spray of GL water. There was no peeling of the water bubble film. As mentioned above, GL water showed a fast-acting effect on burn blisters.
[0035]
(2) A woman (57 years old) accidentally poured hot water between the second and third fingers of her right hand at 6:30 p.m. Blisters were formed 15 minutes after the injury. Soon completed at Soybean University. One hour later, GL water was sprayed and applied to the water bubble portion, and the water bubble shrunk and completely disappeared in 4 to 5 minutes. The next day, no blisters could be identified, but only one spray of GL water was added. On the 6th day after the injury, the skin with scars of the blisters had healed, and the patient did not recognize the presence of the blisters. Generally, when the blisters peel off, they experience a sore and unpleasant 3 to 4 days, but they are completely absent and painless.
[0036]
(3) At 6 o'clock in the morning, a woman (age 52) suffered a hot oil burn between her first and second left fingers. Water bubbles appeared within minutes. Although the affected area was kept under gauze, the pain was severe and GL water was sprayed and applied about 2 hours after the injury. Immediately after the GL water spray, the blisters began to shrink. When the second spraying was further performed one hour later, the water bubbles had completely disappeared, but the last spraying was performed at 6:30 at night and 12 and half hours after the injury, and complete healing was confirmed.
[0037]
Example 3: Case of healing the pressure sore with GL water The patient's physical background was very poor, and the intractable ulcer pressure sore was healed in a short time by spraying and applying GL water. Describe the case.
The study was performed on a female patient (93 years old) with severe cerebral vascular dementia with a history of two strokes (rank C24, care degree 4). The patient suffered a pressure sore with a severe ulcer. The ulcer was enlarged and worsened, and granulogenesis was observed once, but the ulcer expanded again. By repeating such a process, the general condition deteriorated and the pressure sore also deteriorated ((1) in FIG. 1, a photograph on the fourth day after treatment twice daily with GL water). A summary of wound treatment with GL water for this patient is described below.
[0038]
The wound surface was washed with physiological saline, and GL water was sprayed extensively on the wound surface. Then, a small droplet of GL on the wound surface was spread with sterile gauze so that the spray was applied, and applied to the wound surface. The wound was covered with the gauze and the treatment was completed. GL water was sprayed and applied twice daily for 25 days (total of 50 times).
[0039]
The healing pattern is described step by step. During the first week, the ulcer surface in the central part shrank (Fig. 1 (2)), while the surrounding granulation layer area expanded and the wound surface dried (Fig. 1 (2) and (3)). ). Healing rapidly progressed in less than one month during the entire treatment course ((4) in FIG. 1). The reason why the spraying of the GL water was stopped after 25 days was that healing was completed and treatment was no longer necessary. On the fourth day after the treatment was stopped, the pressure sore was completely healed ((5) in FIG. 1).
[0040]
Comparative Example 1: Comparative Example for Pressure Wound Treatment A past situation in which GL water was not used in the same patient as in Example 3 is described as a comparative example.
The patient was injured by a fracture of the right femoral neck, and a 5 × 5 cm (composed of a necrotic part and an ulcer part) pressure sore developed in the right hip. Thereafter, she was instructed by a dermatologist or treated directly (such as application of aznol or ertasin ointment), but as described above, it prolonged or worsened but did not cure.
The difference between this situation and the post-treatment with GL water described above was evident. The ulcer healing activity and the fibroblast growth factor secretion activity of the GL water are added to the above-mentioned anti-inflammatory effect, and heal the pressure sore.
[0041]
Example 4: Therapeutic effect of GL water on burn edema in rats The burn treatment activity in humans described in Example 2 was demonstrated in animals.
The right hind leg of the rat was immersed in boiling water at 70 ° C. for 5 seconds, and the volume of swelling of the foot edema that appeared was measured. Specifically, a certain portion of the rat's right hind limb was marked using an oil-based black felt pen, immersed in a small aquarium up to the mark, and the amount (weight) of the rising water was measured. The measurement was performed before and 1, 3, and 5 hours after inflammation. FIG. 2 shows the results. As a result, a clear decrease was observed in the GL water group as compared with the control group (PBS group) 5 hours after the peak of the inflammation was considered. Since the same experiment was performed twice using three rats at each measurement point, six rats were used at each point in FIG. In addition, since the skin of the rat's foot is clearly thicker and harder than that of humans, the ability to promote the permeability of GL water to the skin and the permeability of other substances is more effective than that of humans. Is considered difficult to raise.
[0042]
Example 5: Therapeutic effect of GL water on herpes labialis When cold sores developed, GL water was sprayed onto the topical area early and tried at least 5 to 6 times. The herpes papules atrophy within the day, and the next day heals. By performing this local treatment, there were two or three cases in which systemic symptoms did not appear and recovered. In such cases, herpes papules and systemic symptoms disappear for several years. That is, there are cases in which it is considered that systemic symptoms have been completely cured by local therapy with GL water.
[0043]
The above-mentioned utility of GL water is presumed to be due to the comprehensive action of glycyrrhizin such as an anti-inflammatory action, an innate immunity-enhancing action, and an anti-viral action. Glycyrrhizin is known to cross mucosa. At that time, various antigenic substances present on the mucosal surface also stimulate and activate some nonspecific defense mechanisms of the living body as foreign substances entering the body together with glycyrrhizin, and nonspecifically prevent pathogens such as invading viruses and bacteria. You may be attacking.
[0044]
【The invention's effect】
The transdermal preparation of the present invention is useful as an agent for treating and / or preventing bruises, burns or pressure sores, and particularly useful as an aqueous transdermal preparation such as a spray, a gel, a lotion, and a poultice. is there.
[Brief description of the drawings]
FIG. 1 shows the results of an example in which a pressure sore was healed with GL water.
(1): Treatment 4 days: Treatment with GL water twice a day, on the 4th day (2) Treatment 10 days: During the first week, the ulcer surface in the central part was reduced.
(3) 15 days of treatment: The surrounding granulation layer area was enlarged and the wound surface was dry.
(4) The 22nd day of treatment: The whole treatment process was less than one month, and healed rapidly. Spraying of the GL water was stopped after 25 days. This is because healing has been completed and there is no need for treatment.
(5) Treatment day 31: On the fourth day after the treatment was stopped, the pressure sore was completely healed.
FIG. 2 shows the therapeutic effect of GL water on burn edema in rats.

Claims (7)

A transdermal preparation comprising an aqueous solution containing glycyrrhizin as an active ingredient. The transdermal formulation according to claim 1, wherein the aqueous solution is an aqueous solution containing ammonium water. 3. The transdermal formulation according to claim 1, wherein the aqueous solution is a hydrophobic converted aqueous solution containing a solvent. The transdermal formulation according to claim 3, wherein the solvent is glycerin and ethanol. The transdermal formulation according to claim 4, wherein the concentration of glycyrrhizin in the aqueous solution is 0.01 to 5% by weight. The transdermal preparation according to any one of claims 1 to 5, wherein glycyrrhizin is obtained by purifying the licorice extract by HPLC. The transdermal preparation according to any one of claims 1 to 6, which is used for treatment and / or prevention of bruises, burns or pressure sores.

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