HK1060981B - External preparations for treating dermatitis - Google Patents

Description

External preparation for treating dermatitis

Technical Field

The present invention relates to an external preparation for treating dermatitis, which is particularly effective for atopic dermatitis and seborrheic dermatitis and has extremely high safety.

Background

Conventionally, steroid preparations such as adrenocorticoid having a high anti-inflammatory action have been mainly used for the treatment of dermatitis such as atopic dermatitis. The steroid preparation may be added with vaseline, methylcellulose, surfactant, synthetic resin emulsion, powder, etc., and is often used in the form of cream according to its purpose. There is also a case where the surfactant is used in the form of a liquid.

On the other hand, as other external preparations, there are highly safe external preparations for the purpose of (i) sterilization and disinfection of the skin, (ii) a skin membrane effect, (iii) an effect of preventing evaporation of skin moisture to promote moisturizing, and the like. Such external preparations may be added as additives to the external preparations, and examples of the additives to the external preparations include those using inorganic salts such as sodium chloride (U.S. p.3574854), those using natural sugars such as glucose (U.S. p.3859436), and those using blood plasma (U.S. p.3777597).

The present inventors have invented an external preparation for treating dermatitis, which is effective for atopic dermatitis, seborrheic dermatitis, eczema and the like and has extremely high safety (Japanese patent publication No. 2920611). The topical preparation contains cyclodextrin coated adrenal cortex steroid, and polysaccharide such as dextran or amylopectin, which will not hinder skin physiological function, and can make natural healing force of organism generate synergistic enhancement effect with adrenal cortex steroid.

Disclosure of Invention

However, adrenocorticosteroids have strong pharmacological effects such as inhibition of fibroblast proliferation and anti-inflammatory action, but no significant effect is known for the treatment of atopic dermatitis. The reason is not known so far, and there is a statement that the reason is that on the oil component for forming an ointment or cream, the oil component dissolves the stratum corneum of the skin, preventing healthy skin from regenerating. In addition, the multi-purpose adrenocortical steroid preparation may suppress side effects such as pituitary gland, adrenocortical function, and dysfunction of other organs and eyes. To solve the above-mentioned side effects, it is desired to reduce the amount of steroid preparations used today while retaining a high pharmacological effect as an anti-inflammatory agent.

Further, although the use of highly safe external preparations such as sodium chloride can achieve the purpose of skin sterilization and skin care such as softening and lubricating the skin and keeping the skin clean, no effect has been found in the treatment of dermatitis such as atopic dermatitis.

On the other hand, the external preparation for treating dermatitis, which was invented by the present inventors, can prevent the blocking of intracellular respiration and the reduction of ATP (adenosine triphosphate) production as a cell energy source due to the mitochondrial membrane disorder, maintain the electrolyte balance and osmotic pressure balance, and effectively exert the pharmacological effects of adrenocorticosteroids. As a result, it has a wide therapeutic effect on many symptoms such as atopic dermatitis, seborrheic dermatitis, psoriasis vulgaris, eczema, and acne. However, among the above-mentioned cured symptoms, the effective rate of seborrheic dermatitis, eczema, whelk, etc. is 96% or more on average, the effective rate of atopic dermatitis is about 95% on average, and the effective rate of psoriasis vulgaris is only 90%.

That is, although it shows a stable and excellent effect on seborrheic dermatitis, eczema, whelk, etc., it has a difference in the effect on atopic dermatitis, and the therapeutic effect on psoriasis vulgaris is inferior to the therapeutic result on other symptoms.

Accordingly, an object of the present invention is to provide an external preparation for treating dermatitis, which is improved in the conventional external preparation for treating dermatitis and has a higher therapeutic effect particularly on atopic dermatitis and psoriasis vulgaris.

In order to achieve the above object, the first aspect of the present invention provides an external preparation for treating dermatitis, which comprises an adrenal corticosteroid coated with cyclodextrin, wherein the adrenal corticosteroid is dissolved in an aqueous solution containing a polysaccharide, the aqueous solution containing the polysaccharide and 0.05 to 0.12 wt% of the adrenal corticosteroid, 5 to 15 wt% of the cyclodextrin, and 3 to 10 wt% of dextran or pullulan, and the external preparation further contains 11.74 to 38.5 wt% of a polysaccharide selected from the group consisting of xyloglucan, trehalose, laminaran, polysaccharide K, and pectin. At this time, the adrenal corticosteroid was dissolved and coated by a homogenizer at room temperature, and then added to the aqueous solution uniformly while stirring.

In the 2 nd embodiment, glucose, water-insoluble poly (. alpha. -1, 3-glucose) (mutan), lentinan, sodium chloride, and potassium chloride are further added to the aqueous solution. Since the aqueous solution can generate the same environment in cells as interstitial fluid and promote normal activities of cells, the natural healing force of the body can generate synergistic enhancement effect with the adrenal cortex steroid preparation.

The basic formulation of the present invention is to dissolve the adrenocorticosteroid in an aqueous solution containing a polysaccharide. In order to dissolve a poorly water-soluble adrenal corticosteroid in an aqueous solution, the adrenal corticosteroid is coated with cyclodextrin in advance.

As adrenal corticosteroids, diflorasone, hydrocortisone, methylprednisolone, dexamethasone, betamethasone, and the like are mainly used. The content of the compound is 0.025-5% of the total weight. The cyclodextrin coated with the adrenal cortex steroid accounts for 0.2-40% of the total weight.

And 0.5-55 wt% of xyloglucan, trehalose, laminaran, polysaccharide K and pectin.

Xyloglucan is a structural sugar chain widely present in the wall (primary wall) of elongated, hypertrophied plant cells. Specificity of the plant species is produced by the binding of galactose or fucosyl-galactose to xylose residues. The galactose residue and the fucose residue can be bound with lectins, respectively, but the functions of these branched sugar chains are not known. The growth of plant cells is caused by the phenomenon of water absorption due to osmotic pressure of the cells, and water absorption is caused by a decrease in wall pressure due to relaxation of cell walls. The mechanism of cell wall relaxation is not clear, but cell elongation is always accompanied by the decomposition and solubilization of xyloglucan, and xyloglucan has been attracting attention as one of polysaccharides that dominate the physiological activities of cells.

Laminarin is a hydrocarbon belonging to the group of beta-glucans. The extract is prepared from mushroom such as Lentinus Edodes, and Sargassum such as thallus laminariae, and has immunity enhancing effect. It is known to be difficult to absorb alone and is preferably taken with proteins.

Polysaccharide K is used as an immunotherapeutic agent for enhancing the expression of HLA class I antigen of human cancer cells, and is extracted from mycelia of Hericium erinaceum. Polysaccharide K is found to have an immunotherapeutic effect on tumor diseases such as gastric cancer, colon cancer, rectal cancer, small cell lung cancer and the like.

Trehalose is a sugar substance and exists in mushrooms, seaweeds, bakers' yeasts and the like, and artificial synthesis methods thereof have been recently studied. Is used as a humectant, a substitute for a sweetener, etc., but in the present invention, is used as an external agent ingredient for dermatitis by combining with other sugar ingredients.

Pectin is known as a structural component of plant cell walls, and is a natural polysaccharide that binds to components such as cellulose and links cell membranes. Pectin is used as a gelling agent, a viscosity-increasing agent, and a stabilizer.

The present inventors studied components suitable for external preparations among many polysaccharides, and as a result, prepared external preparations effective for atopic dermatitis and seborrheic dermatitis by combining xyloglucan, trehalose, laminarin, polysaccharide K, and pectin.

And adding a polysaccharide to the aqueous solution in which the corticosteroid is dissolved. The polysaccharide is dextran or amylopectin, and accounts for 0.5-60% of the total weight. In addition, glucose, water-insoluble poly (. alpha. -1, 3-glucose), lentinan, sodium chloride, and potassium chloride are added to the aqueous solution in which the adrenal corticosteroid is dissolved.

Detailed Description

The external preparation of the present invention will be specifically described below by referring to prescription examples and pharmacological test examples.

Formulation example 1

Glucan 3(g)

Glucose 5

Maltose 5

Mannitol 15

Sodium chloride 0.2

Betamethasone 0.06

Cyclodextrin 15

Xyloglucan 2

Trehalose 3

Laminaria japonica polysaccharide 2.5

Polysaccharide K3

Pectin 1.24

Pure water 45

Total amount of 100.0g

In the above formulation example, a 10% cyclodextrin solution was prepared from a part of pure water, betamethasone was added to the solution while stirring, and then xyloglucan, trehalose, laminaran, polysaccharide K, pectin, and the rest of pure water and salt were added together.

The effects of formulation example 1 are shown below.

TABLE 1

Pathological state	Number of subjects	Effectiveness of	High efficiency	Compared with the previous time
					Atopic dermatitis (1)	50	98	98	+2
Atopic dermatitis (2)	24	46	96	+1
					Atopic dermatitis (3)	56	110	98	+6
Atopic dermatitis (4)	25	49	98	0
					Seborrheic dermatitis (1)	43	80	93	-3
Seborrheic dermatitis (2)	78	149	96	-3
					Seborrheic dermatitis (3)	10	18	90	-5
Psoriasis vulgaris	10	19	95	+5
					Eczema (eczema)	15	28	93	-3
Whelk	50	96	96	-3

Table 1 shows the results of pharmacological tests of formulation example 1. From these results, the most notable effective rate for atopic dermatitis in the present invention was 96 to 98%, and the average was 97.5%. Namely, the efficiency is high and there is no variation.

On the other hand, the effective rate for psoriasis vulgaris is 95%, and the effective rate for atopic dermatitis is not as good, but a quite good therapeutic effect is shown. It is worth mentioning that in 300 cases, there are no 1 side effect. This feature has been demonstrated in the prior external preparations, and the safety of the external preparations after this improvement has been confirmed.

The effectiveness at this time was calculated based on the following criteria and the following formula: after the external preparation of the present invention is used, the score is 0 when there is no change, 1 when there is a change in the direction of healing, and 2 when there is an effect, the total score of each person is obtained.

The results of pharmacological tests conducted in clinics of Mount Liangshan, Xiantai, Dagong and Guique are listed for atopic dermatitis, and the other items are data of pharmacological tests conducted in clinics of Mount Liangshan.

The results of pharmacological tests in formulation example 1 all showed a cure-improving effect with an effective rate of 90% or more, and the external preparation of the present invention was not needed after about 7 to 30 days, the fastest. The patient is then coated with an aqueous solution containing a polysaccharide obtained by removing the adrenal corticosteroid (Japanese patent No. 1597430), and the treatment is completely completed. In this application, the skin moisturized feel was evaluated as "good, normal, poor" in three ways, and the results are as follows.

TABLE 2

	Good effect	General purpose	Difference (D)
				Number of people (human)	3 56	14	0
Ratio (%)	96.2	3.8	0.0

None of the results was evaluated as poor, and 96% or more of the results were evaluated as good in touch feeling during use.

Prescription example 2

Glucan 10(g)

Glucose 5

Maltose 10

Mannitol 5

Sodium chloride 0.1

Potassium chloride 0.2

Betamethasone sodium phosphate 0.12

Cyclodextrin 10

Xyloglucan 2

Trehalose 8

Laminaria polysaccharide 6

Polysaccharide K4

Pectin 12

Pure water 27.58

Total amount of 100.0g

Formulation example 3

Amylopectin 10(g)

Betaine 15

Maltose 10

Sodium chloride 0.1

Dexamethasone 0.06

Cyclodextrin 15

Xyloglucan 6

Trehalose 3

Laminaria japonica polysaccharide 2

Polysaccharide K6

Pectin 3

Pure water 29.84

Total amount of 100.0g

Prescription example 4

Glucan 5(g)

Betaine 20

Maltose 5

Sodium chloride 0.1

Dexamethasone sodium phosphate 0.05

Cyclodextrin 6

Xyloglucan 2

Trehalose 5

Laminaria japonica polysaccharide 7

Polysaccharide K2

Pectin 8

Pure water 39.75

Total amount of 100.0g

Formulation example 5

Glucan 10(g)

Hydroxyethyl cellulose 2

Betaine 10

Mannitol 10

Sodium chloride 0.1

Calcium chloride 0.1

Dexamethasone sodium phosphate 0.1

Cyclodextrin 10

Xyloglucan 10

Trehalose 7

Laminaria japonica polysaccharide 10

Polysaccharide K2

Pectin 8

Pure water 20.7

Total amount of 100.0g

Prescription example 6

Amylopectin 10(g)

Hydroxyethyl cellulose 6

Betaine 10

Mannitol 5

Calcium chloride 0.1

Sodium chloride 0.1

Dextrin 7

Dexamethasone 0.05

Cyclodextrin 5

Xyloglucan 6

Trehalose 9

Laminaria polysaccharide 6

Polysaccharide K9

Pectin 8.5

Pure water 18.25

Total amount of 100.0g

It can be seen that the results of the above-described prescription examples 2 to 6 complied with the effect of prescription example 1. These formulations can be appropriately selected according to the symptoms of dermatitis.

The conventional prescription and pharmacological effects thereof will be described in comparison.

Prescription example 7 (conventional prescription)

Glucan 10(g)

Glucose 10

Maltose 5

Mannitol 15

Sodium chloride 0.2

Betamethasone 0.06

Cyclodextrin 15

Pure water 44.74

Total weight 100.0g

TABLE 3

Pathological state	Number of subjects	Effectiveness of	High efficiency
				Atopic dermatitis (1)	25	48	96
Atopic dermatitis (2)	10	19	95
				Atopic dermatitis (3)	25	46	92
Atopic dermatitis (4)	25	49	98
				Seborrheic dermatitis (1)	25	48	96
Seborrheic dermatitis (2)	100	198	99
				Seborrheic dermatitis (3)	10	19	95
Psoriasis vulgaris	5	9	90
				Eczema (eczema)	25	48	96
Whelk	50	99	99

Table 3 shows the results of pharmacological tests (the method of calculating the efficacy and the clinical practice of the pharmacological test are the same as those in Table 1) in prescription example 7 (conventional prescription). From the results, it was found that the average effective rate for seborrheic dermatitis, eczema, acne and the like was 96% or more, but the effective rate for atopic dermatitis was about 95% on average and the effective rate for psoriasis vulgaris was only 90% using the conventional prescription.

In addition, in the formula example 1, xyloglucan, trehalose, laminarin, polysaccharide K and pectin are added, so that the therapeutic effect on atopic dermatitis and psoriasis vulgaris is improved.

The present invention achieves the first object by the above constitution.

That is, the present invention provides an external preparation for treating dermatitis, which comprises an aqueous solution containing a polysaccharide, wherein an adrenal corticosteroid is coated with cyclodextrin, 0.025 to 0.5 wt% of the adrenal corticosteroid, 0.2 to 30 wt% of the cyclodextrin, and 0.5 to 55 wt% of dextran or pullulan are dissolved in the aqueous solution, and 0.5 to 55 wt% of xyloglucan, trehalose, laminaran, polysaccharide K, and pectin are added to the aqueous solution, whereby a stable and excellent effect of treating atopic dermatitis can be obtained, and the external preparation for treating dermatitis has a variation from the conventional external preparations.

In addition, the effective rate of psoriasis vulgaris, which had been treated less effectively than other symptoms, can be improved to the level equivalent to other cases.

Thus, the present invention has a greatly improved efficacy as compared with conventional external preparations, and is particularly effective for treating diseases which are difficult to improve, such as atopic dermatitis and seborrheic dermatitis, and has a high cure rate and few side effects, and can replace conventional external preparations in terms of safety. Is expected to be used by a plurality of patients with intractable dermatitis in the world. The invention has great significance and makes important contribution to human.

Claims (2)

1. An external preparation for treating dermatitis, which comprises an aqueous solution containing dextran or pullulan and an adrenal corticosteroid coated with cyclodextrin, wherein the aqueous solution contains 0.05 to 0.12 wt% of the adrenal corticosteroid, 5 to 15 wt% of cyclodextrin, and 3 to 10 wt% of the dextran or pullulan dissolved therein, and further contains 11.74 to 38.5 wt% of a polysaccharide comprising xyloglucan, trehalose, laminaran, polysaccharide K and pectin, based on the total weight of the aqueous solution.

2. The external preparation for treating dermatitis according to claim 1, wherein said aqueous solution further contains one or more of glucose, water-insoluble poly (a-1, 3-glucose), lentinan, sodium chloride, and potassium chloride.