KR20040034795A - Epidermal formulation comprising steroid medicaments and placenta extract for treatment of inflammatory dermatoses - Google Patents

Abstract

PURPOSE: Provided is an epidermal formulation for treatment of inflammatory dermatoses, which comprises, an active ingredient, a pharmaceutically effective amount of steroid medicaments and an placenta extract, as well as a pharmaceutically acceptable carrier. CONSTITUTION: A epidermal formulation for treatment of inflammatory dermatoses comprises, an active ingredient, 0.001-5 wt.% of steroid medicaments and 0.0005-20 wt.% of an placenta extract. It further comprises a pharmaceutically acceptable carrier and is formulated into cream, ointment, gel or paste.

Description

Percutaneous cure for inflammatory skin disease containing steroid preparations and placental extracts {EPIDERMAL FORMULATION COMPRISING STEROID MEDICAMENTS AND PLACENTA EXTRACT FOR TREATMENT OF INFLAMMATORY DERMATOSES}

The present invention relates to a transdermal agent for treating inflammatory skin diseases containing steroid medicaments and placental extracts. More specifically, the present invention relates to a transdermal agent useful for treating various types of inflammatory skin diseases by mixing a pharmaceutically effective amount of a steroid preparation and a placental extract as an active ingredient, together with a pharmaceutically acceptable carrier.

US Pat. No. 4,070,462, US Pat. No. 4,489,701, and US Pat. No. 4,298,604 and the like describe the high anti-inflammatory effects of steroid-containing transdermal agents and are well known in the art. Drugs most widely used for the treatment of such inflammatory diseases are known as glucocorticosteroids or glucocorticoids as corticosteroids. About 50% of those prescribed for inflammatory skin diseases are for topical corticosteroids, and since the substance has been introduced into skin diseases since the early 1950s, topical corticosteroids have been used in various skin disease treatment techniques. On the other hand, although systemic corticosteroids are often used for some serious skin diseases, topical corticosteroids are preferred for the treatment of most skin diseases because topical treatments do not cause systemic adverse effects.

Topical corticosteroids are generally effective for acute and chronic skin diseases such as seborrheic dermatitis, atopic dermatitis, irritant and allergic contact dermatitis, topical neurodermatitis (chronic simple thyroiditis), squamous and psoriasis. Conventional topical corticosteroid therapies and therapeutic effects are described in the following literature (Drugs 36, Appendix 5, adis press Ltd., 1-61, 1988).

The efficacy of such corticosteroid formulations depends on the particular corticosteroid selected, its concentration and its excipients. In general, topical corticosteroids are divided into seven groups according to efficacy. This classification is graded according to relative potency, with very high efficacy groups I, high efficacy groups II and III, medium efficacy groups IV and V, and low efficacy groups VI and VII (RB Stoughton, Annual Review of Pharmacologic Toxicology, 59-60, 1989). Representative commercialized corticosteroid formulations are listed in Table 1 below according to efficacy grade.

Efficacy rating of topical corticosteroids (highest potency group I to lowest potency group Ⅶ) Efficacy rating Common name Dosage form Normal concentration I Betamethasone dipropionic acid Cream, ointment 0.05% Clobetasol propionic acid Cream, ointment 0.05% Diflorason Diacetic Acid Ointment 0.05% Ⅱ Amsinonide Cream, ointment 0.1% Betamethasone dipropionic acid Ointment 0.05% Diflorason Diacetic Acid Ointment 0.05% Halsinoid Cream, ointment 0.1% Fluorinide Creams, ointments, liquids, gels 0.05% Desoxymethasone Cream and Gel Ointment 0.05 to 0.25% Triamcinolone Acetonide Cream, ointment 0.5% Mometasone Ointment 0.1% Fluorcinolone Acetonide cream 0.2% Ⅲ Triamcinolone Acetonide Ointment 0.1% Betamethasone dipropionic acid cream 0.05% Diflorason Diacetic Acid cream 0.05% Betamethasone valeric acid Ointment 0.1% Mometasone cream 0.1% Ⅳ Fluandrenolide Ointment 0.05% Triamcinolone Acetonide Cream, lotion 0.1% Fluorcinolone Acetonide Ointment 0.025% Desoxymethasone cream 0.05% Clocotolone pivaleric acid cream 0.1% Ⅴ Fluandrenolide cream 0.05% Betamethasone dipropionic acid 0.05% Triamcinolone Acetonide Lotion 0.1% Hydrocortisone butyric acid Cream, ointment 0.1% Fluorcinolone Acetonide cream 0.025% Betamethasone valeric acid cream 0.1% Hydrocortisone valeric acid cream 0.2% Ⅵ Desonide Cream, ointment 0.05% Fluorcinolone Acetonide Liquid 0.01% Betamethasone valeric acid Lotion 0.05% Aciomethisone dipropionic acid Cream, ointment 0.05% Ⅶ Hydrocortisone, dexamethasone flu metallon, prednisolone and methiprednisolone topical agents

Some steroids, especially medium to high potency steroids, are effective against chronic skin diseases, but prolonged use of steroids can cause serious local side effects. In addition, the use of certain enhancers, such as the treatment of large areas of skin and sealing bandages, can increase the likelihood of adverse effects. This is especially the case for children with a high rate of adverse effects.

Therefore, the present inventors have attempted to develop a transdermal agent that can exhibit an excellent skin disease treatment effect while reducing such side effects.

The present inventors have studied to develop excellent dermatological agents, and found that compositions containing steroid preparations and placental extracts effectively improve or treat various skin diseases, rather than using conventional steroid preparations alone. The present invention was completed by formulating a composition containing a steroid preparation and a placental extract for transdermal use.

Accordingly, the present invention provides a transdermal pharmaceutical composition containing steroid preparations and placental extracts as active ingredients in a pharmaceutically effective amount together with a pharmaceutically acceptable carrier, which is useful for ameliorating or treating inflammatory skin diseases.

Particular steroid agents useful in the compositions of the present invention are corticosteroids and include all corticosteroids whose anti-inflammatory activity is known. Preferably medium to high potency corticosteroids can be used, most preferably betamethasone dipropionic acid. In addition, certain chronic dermatological diseases (eg, atopic dermatitis) that do not require high potency steroids may be used with low potency corticosteroids. Corticosteroids that can be used in the present invention are listed according to efficacy in Table 1 above (see Table 1).

Placenta extract containing a lot of useful components to the human body as another useful component of the present invention is known to contain all the components of the human body, in particular rich in various hormones and amino acids. In addition, placenta extract has been reported to be effective in skin diseases, digestive ulcers, neuroses, menopausal disorders, trauma, acne and allergic diseases from numerous previous studies. It is used for duodenal ulcer and menopausal disorders. In addition, it is well applied in dermatology areas such as autonomic ataxia and various allergic diseases. Research on the usefulness is being conducted. The preparation of the placenta extract can be generally obtained by washing, bleeding, crushing and freezing, extracting the water-soluble part with water, and then removing impurities.

Cord blood, which is a component of the placenta and umbilical cord, can be treated through bone marrow transplantation, from acute leukemia, breast cancer, ovarian cancer, to blood diseases such as aplastic anemia, and immune system defects. It can be applied to all diseases. In particular, umbilical cord blood is rich in hematopoietic stem cells, which produce blood in the same way as bone marrow, and is basically used to replace bone marrow transplantation.

In relation to the effects of placental extracts listed above, the inventors have combined fetal extracts, preferably serum components of umbilical cord blood (hereinafter referred to as "cord serum") with steroidal agents to treat inflammatory skin diseases. As a result of the study, it was found that the therapeutic effect is improved for several skin diseases than the conventional steroid preparation alone.

Accordingly, the present invention provides an inflammatory dermatological transdermal agent wherein the active ingredient is a steroid preparation and a placental extract. The steroid preparation in the active ingredient is a corticosteroid, preferably betamethasone dipropionic acid can be used. Placenta extract of the active ingredient is generally obtained by washing and finening several times using placenta and umbilical cord, preferably human placenta and umbilical cord, such as human or cow, and then adding the purified water and then homogenizing at low temperature. do. More preferably, the placental extract of the active ingredient may be a umbilical cord serum obtained from umbilical cord blood, which is a component of the placenta. Umbilical cord serum is generally obtained by cutting the cord and collecting cord blood from a vein in the umbilical cord connected with the placenta with a syringe and centrifuging the cord blood. ) Cord blood can be obtained from public cord blood banks such as Histostem Co., Ltd., MediPost Co., Ltd., and LifeCode Co., Ltd., and serum can be obtained after centrifugation.

In a preferred embodiment, the present invention is a pharmaceutical composition containing, as an active ingredient, a steroid agent and placental extract in a pharmaceutically effective amount together with a carrier which is acceptable for it to be formulated for transdermal administration. As used herein, the term "pharmaceutically effective amount" means an amount of the active ingredient that has an improvement or therapeutic effect on inflammatory skin disease. The term "transdermal administration" means topically administering the pharmaceutical composition to the skin to deliver a therapeutically effective amount of the active ingredient contained in the pharmaceutical composition into the skin. The term “pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable substance such as a liquid or solid filler, diluent, excipient or solvent which serves to transport the active ingredient from one organ or part of the body to another organ or part of the body. , Composition or vehicle.

The therapeutically effective amount of an active steroid agent in the transdermal formulation of the present invention may vary depending on the patient's age, sex, skin condition, site of application, frequency of administration, time of administration, dosage form, type of adjuvant, etc. Wt%, preferably about 0.01 to 1 wt%.

In addition, the therapeutically effective amount of the other active ingredient, placenta extract may vary depending on the age, sex, skin condition, site of application, frequency of administration, time of administration, dosage form, type of adjuvant, etc., but generally about 0.0005 to 20% by weight, Preferably from about 0.001% to 10% by weight.

The transdermal agent of the present invention containing the above active ingredient may generally exhibit improvement or treatment effects by applying an appropriate amount to the skin disease site once or twice a day for about 2 to 3 weeks.

Inflammatory skin diseases that can be treated by the transdermal agents of the present invention are well known in the art. Inflammatory vulgaris, for example; Inflammatory rounded acne; Lichen planus (especially hypertrophic deformation); Discotic lupus erythematosus; Disc lupus erythema; Atopic dermatitis; Contact or allergic dermatitis; Hand dermatitis; Genotypic lichens; Alopecia areata; False beard folliculitis; Pore red nasal cavity; Fungal carcinomas and drug reactions (acute).

Transdermal preparations according to the present invention include creams, ointments, lotions, gels, external solutions, pasta, linings, external acids, aerosols and transdermal absorbents. These formulations are described in Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania, 18042, Chapter 87: Blaug, Seymour, a prescription generally known in all pharmaceutical chemistries.

Representative creams of the present invention include cold creams, emollient creams, shaving creams, varnishing creams, hand creams, and the like, and are generally applied as an oil-in-water type (o / w) system containing stearic acid and water. After that the varnishing cream which evaporates water and leaves a thin film of stearic acid is preferably used. Cold cream may also be suitably used, which is a semi-solid white water-in-oil base (w / o) formulation prepared with cetyl, alcohol, beeswax, white lead, circulating paraffin, sodium borate and purified water. Ointments of the present invention may be classified into hydrocarbon bases, absorbent bases, flushable bases and water-soluble bases depending on the type of base used therein, but all of them are well known to those skilled in the formulation art. The lotion agent of the present invention is classified into suspension and emulsion, and is usually prepared using an emulsifier or other suitable stabilizer. All of which are well known to those skilled in the formulation art and are included in the present invention.

Referring to the above description, a method for preparing a transdermal drug according to the present invention will be described as an example of a cream, an ointment, a gel, and a pasta.

Representatives used as transdermal agents include creams, which are alcohols, beeswax, sorbitan monooleate, steroid preparations and fetal vertebral serum, sorbitol solution, polysorbate, methylparaben, propyl An aqueous phase consisting of a mixed solution of paraben, glycerin, methylparaben, propylparaben, potassium hydroxide and purified water is separately heated to 65 to 75 ° C, and the oil phase is gradually added to the aqueous phase and stirred to form a crude emulsion. The emulsion thus formed can be obtained by cooling to a temperature where volatilization and decomposition do not occur, homogenizing and stirring at a constant speed until solidifying.

Ointments can be prepared on a large or small scale, and special preparations will depend greatly on the nature of the ingredients. In small-scale preparations of ointments, incorporation may be used in which the ointment is mixed in several ways until a uniform formulation is obtained.In large-scale preparations, all or part of the ointment is melted and then melted. Melting, cooling and mixing with stirring at a constant speed until solidification can be used. At this time, the components that do not melt usually requires a process of mixing while cooling. In general, thermally unstable substances or volatile substances will produce an ointment in the low temperature range where the temperature of the mixture does not cause decomposition or volatilization of the components.

The gel agent is dispersed in metocell in purified water heated to 80 to 90 ℃ and then left for about 12 hours, the gel composition is dispersed in the purified purified water to prepare a dispersion. Then, sodium hydroxide solution is added to the dispersion to adjust to neutral pH. Methyl paraben, methocell, carbocol, propylene glycol and the like are mixed with the dispersion thus prepared to obtain a gel.

The pasta agent can be prepared by incorporating the pasta composition into a predetermined container such as a mortar and powder, and then uniformly mixing the petrolatum or the like.

Steroid preparations and fetal cord serum as active ingredients in the transdermal formulations of the present invention can promote absorption into the skin by known physical and chemical methods. Physical methods using mainly heat, electricity and ultrasonic energy may be suitable, but preferably chemical methods may be used. Transdermal absorption accelerators that can be used in the chemical process according to the present invention include those listed in Table 2 below.

Types and types of representative transdermal absorption accelerators Group of chemical absorption accelerators Example of use Nonionic Twins, Brij, Spans, Triton X-100, Polozymer Surfactant Anionic Sodium lauryl sulfide Drift Cationic N, N-bis (2-hydroxyethyl) oleylamine Sulfoxide DMSO, dodecylmethyl sulfoxide (DCMS), DMF Esoxylate Dodecanol, Hexoxylate Solvents Alcohol ethanol Polyolith Propylene Glycol, Polyethylene Glycol, Glycerin Pyrrolidones PVP, 2-pyrrolidone, N-methyl-2-pyrrolidone Fatty Fatty acids Oleic acid, linolenic acid, lauric acid, myristic acid, stearic acid, IPM, IPP, caric acid, capric acid Fatty alcohols Olyl, Lauryl, Stearyl Zwitter Onyx Dodecyldimethylaminopropane sulfate amides n, n-diethyl-m-taumidamide (DEET) Urea Urea, 1-dodecylurea, 1,3-didodecylurea, 1,3-diphenylurea Terpenes Eucalyptol, menthol, limonoxide Lactams Laurocapram (Azon) Cheratos Disodium EDTA Bile salt Glycocholate, Calcium Thioglycolate Macrosalicynic Macrosalicylic ketone / lactone

Hereinafter, the formulation and preparation of the medicament according to the present invention are specifically illustrated by Examples. However, these examples should not be understood as limiting the present invention.

<Example 1>

Cream

Paid

Stearic acid 13 wt%

Stearyl Alcohol 1% by weight

Cetyl Alcohol1 wt%

Betamethasone dipropionic acid0.05 wt%

Umbilical cord serum 5% by weight

Awards

Glycerin 10 wt%

Methylparaben 0.1 wt%

Propylparaben0.05 wt%

Potassium Hydroxide0.9 wt%

100% of purified water

The oil phase and the water phase were separately heated to 65 ° C. and the oil phase was slowly added to the water phase and stirred to form a crude emulsion. The emulsion formed was cooled to about 50 ° C. and homogenized. Cooling with shaking until the homogenate condensation gave a cream.

<Example 2>

Ointment

Vaseline 80 wt%

Stearyl Alcohol 3% by weight

Pewter8.95 wt%

Cholesterol3 wt%

Betamethasone dipropionic acid 0.05% by weight

Umbilical cord serum 5% by weight

Stearyl alcohol, pewter, betamethasone dipropionic acid, umbilical cord serum and cholesterol were dissolved in a steam bath and petrolatum was added. Heating was continued slowly until a liquid formed. The ointment was obtained by condensation by stirring and cooling.

<Example 3>

Gel

Methocel 90 H.C. 40000.8 wt%

Carbocol 9340.24 wt%

Propylene Glycol 16.7 wt%

Methylparaben0.015 wt%

Betamethasone dipropionic acid 0.05% by weight

Umbilical cord serum 5% by weight

Sodium hydroxide pH7 adjustment amount

100% of purified water

Methocel was dispersed in 40 ml of hot (80-90 ° C.) water and cooled in the refrigerator overnight to make a solution. 20 ml of Carbocol 934, 0.05% betamethasone dipropionic acid and 5% umbilical cord serum were dispersed in water and the pH was adjusted to 7.0 by adding sufficient 1% sodium hydroxide solution to the dispersion. Purified water was added to make a 40 ml volume. Methylparaben was dissolved in propylene glycol. Methocel, carbocol 934 and propylene glycol fractions were mixed to obtain a gel.

<Example 4>

Pasta

Zinc oxide 25 wt%

Starch 25% by weight

Calamine 5% by weight

Betamethasone dipropionic acid0.05 wt%

Umbilical cord serum 5% by weight

Vaseline 100% Composition

Calamine was titrated with zinc oxide, betamethasone dipropionic acid, umbilical cord serum and starch, powdered in a mortar and mixed uniformly in petroleum jelly to obtain a pasta agent.

The laboratory examples below illustrate that the transdermal agents according to the present invention exhibit an improvement and / or therapeutic effect on inflammatory skin diseases. However, the following laboratory examples merely exemplify the effects of the present invention, and it will be understood by those skilled in the art from these exemplary experimental results that the transdermal agents of the present invention can be effectively used to ameliorate and / or treat inflammatory skin diseases.

Experimental Example

Laboratory Example 1

Thirty patients with severely inflammatory vulgar acne were applied to each skin with the cream of Example 1. As a result, these patients were treated within two to three weeks with twice daily application.

Laboratory Example 2

Six patients with hypertrophic lichen planus of the leg were applied to each skin with the cream of Example 1. As a result, these patients were treated within 3 weeks with twice daily application.

Laboratory Example 3

Ten adults with adult-type chronic atopic dermatitis, which appear as chronic simple tachycardia on the lower legs, were applied to each skin with the ointment of Example 2. As a result, conditions characterized by pruritus thick plaque essentially disappear within three weeks with twice daily application of the formulation.

Lab Example 4

A small number of patients with various chronic skin diseases characterized by chronic, resistant, and inflammatory lesions applied the gels and pastas of Examples 3-4 daily for three to four weeks. Confirmed to heal.

Transdermal agents containing steroid preparations and placental extracts as active ingredients according to the invention exhibit an effect of improving or treating inflammatory skin diseases.

Claims (7)

A transdermal agent for treating inflammatory skin disease, which comprises as an active ingredient a steroid preparation and placental extract in a pharmaceutically effective amount together with a pharmaceutically acceptable carrier. The transdermal agent according to claim 1, which contains as an active ingredient 0.001 to 5% by weight steroid preparation and 0.0005 to 20% by weight placenta extract. The transdermal drug according to claim 1, wherein the steroid agent in the active ingredient is a corticosteroid selected from the group consisting of I to V in Table 1. 4. The transdermal agent of claim 3, wherein the corticosteroid is betamethasone dipropionic acid. The transdermal drug according to claim 1, wherein the placental extract of the active ingredient is umbilical cord serum. The method of claim 1, wherein the inflammatory skin disease comprises inflammatory vulgaris; Inflammatory rounded acne; Lichen planus (especially hypertrophic deformation); Discotic lupus erythematosus; Disc lupus erythema; Atopic dermatitis; Contact or allergic dermatitis; Hand dermatitis; Genotypic lichens; Alopecia areata; False beard folliculitis; Pore red nasal cavity; A transdermal agent selected from the group consisting of mycelial sarcoma and drug response (acute). The transdermal formulation according to claim 1, wherein the transdermal formulation is a cream, ointment, gel or pasta.