JP2007530481A - Pharmaceutical composition for the treatment of skin diseases comprising a combination of epinastine and one or more additional minerals or one or more herbal medicines - Google Patents

Abstract

  The present invention relates to a pharmaceutical composition for the treatment of skin diseases. Specifically, the composition according to the present invention is quite effective for the treatment of skin diseases associated with allergic reactions among various symptoms derived from skin diseases. These compositions comprise an antihistamine effective amount of epinastine or a pharmaceutically acceptable salt thereof and one or more additional pharmaceutically acceptable minerals or one or more pharmaceutically acceptable herbal medicines. including. The composition may also contain pharmaceutically acceptable additives.

Description

The present invention relates to a pharmaceutical composition for the treatment of skin diseases. Specifically, the composition described in the present invention is very effective in the treatment of skin diseases related to allergic reactions among various symptoms derived from skin diseases. In a first aspect, these compositions comprise an antihistamine effective amount of epinastine or a pharmaceutically acceptable salt thereof and one or more additional pharmaceutically acceptable minerals as a pharmacologically active compound. including. In a second embodiment, these compositions comprise an antihistamine effective amount of epinastine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable herbal medicines as a pharmacologically active compound. . The composition may also contain pharmaceutically acceptable additives.
The present invention further relates to the use of these compositions for the treatment of skin diseases such as urticaria, eczema and skin rash, pruritus and pruritus from pruritus vulgaris.

In recent years, progressive skin related to allergic reactions due to increased exposure to environmental chemicals due to various factors such as changes in diet and lifestyle, air pollution, deterioration of environmental conditions, and increased stress from social life, etc. The incidence of disease is increasing. These skin diseases associated with allergic reactions include urticaria, eczema, skin irritation and dermatitis. Itchy skin diseases represented by pruritus, prurigo and psoriasis vulgaris are numerous.
Urticaria, also known as wheal, is a transient edema. The disease is characterized by a sudden onset of itching sensation in the skin, followed by a clear rash-like progression of wheal and growth from nail to palm size exacerbated by scratching behavior.

The symptoms may disappear within minutes to hours and may not leave any skin symptoms, but an advanced episode to the rash may recur. Causes of urticaria include self-sensitization, sensitization related to dysmenorrhea, pregnancy, food, medicine and insect bites, abnormal responses to heat, chills, mechanical stimulation and light, remote response to bacterial sensitization, gastrointestinal tract, liver And kidney disease, involvement of endocrine disorders, and psychological factors.
Eczema or dermatitis is the most major skin disease characterized by an inflammatory response of the skin. Eczema and dermatitis are often generally regarded as a group of eczema dermatitis. Often the disease is an external stimulus (many chemicals, fragrances, metals, detergents, drugs, plants, bacteria, insects, sunlight, heat, chills, dryness), internal abnormalities (local abnormalities such as sweating) , Abnormal sebum secretion, abnormal keratosis, and systemic abnormalities such as atopy, sensitization sites, digestive disorders, renal failure, endocrine disorders) and pathological interactions caused by physical conditions. Eczema dermatitis groups include contact dermatitis, atopic dermatitis, seborrheic eczema, monetary eczema, autosensitizing dermatitis and chronic simple lichen vidal.

Housewives eczema, progressive palmokeratosis, diaper dermatitis and photocontact dermatitis are classified as general contact dermatitis. In addition, the group includes diffuse neurodermatitis, stasis dermatitis, eczema-like infectious dermatitis, and perioral dermatitis. The wide area also includes radiation dermatitis, burns, and frostbite.
Pruritus is a disease characterized by the development of itching sensation (itching) in apparently normal skin. Pruritus in the affected area is divided into general pruritus and local pruritus. The disease originates from a variety of causes and often progresses as a symptom of systemic disease.

  Urticaria is a papule or urticaria-like nodule that develops extreme itching and develops into a chronic or recurrent symptom, such as acute urticaria, e.g. childhood stroflus, urticaria-like lichen, summer urticaria, acute simple urticaria Can be broadly classified into subacute rashes, such as subacute simple rashes and chronic rashes, such as polymorphic chronic rashes, nodular rashes, Hebra rashes and chronic simple rashes. The mechanism of pathogenesis is not clear. Insect bites are used in acute urticaria, and in chronic urticaria, diabetes mellitus, liver damage, leukemia, Hodgkin's disease, visceral cancer and erythrocytosis are considered to be the causes.

  Psoriasis vulgaris is an inflammatory skin disease that manifests histological features of epidermal proliferative and inflammatory cell infiltration. The rash generally progresses in the head, the extremities of the extremities, and the trunk that appears to be in particular contact with mechanical compression, with pruritus observed in almost half of it. An immune disorder may be related to the cause of the disease.

  It is emphasized that improvement of the surroundings, for example elimination of the causative antigen, is the most important factor for the treatment of these skin diseases, in particular allergic skin diseases. Nevertheless, as already outlined, etiology is often difficult to confirm because it is variable and complex. Accordingly, compositions that combine antihistamine compounds are often selected for the treatment of these symptoms, including itchiness resulting from skin diseases.

Objects of the invention The present invention provides, in a first aspect, epinastine or a pharmaceutically acceptable salt thereof for the prevention and / or treatment of skin diseases, preferably skin diseases associated with allergic reactions, and Provided are pharmaceutical compositions and dosage forms comprising one or more additional pharmaceutically acceptable minerals as pharmacologically active compounds, wherein effective improvements are achieved by their apparent utility .
Furthermore, the present invention relates to epinastine or a pharmaceutically acceptable salt thereof and 1 as a pharmacologically active compound for the prevention and / or treatment of skin diseases, preferably skin diseases associated with allergic reactions. Or a pharmaceutical composition and dosage form comprising two or more additional pharmaceutically acceptable crude drugs, wherein an effective improvement is achieved by its apparent utility.

  Furthermore, the present invention provides a pharmaceutical composition comprising epinastine or a pharmaceutically acceptable salt thereof as an active agent for the prevention and / or treatment of skin diseases, preferably skin diseases associated with allergic reactions, and A pharmaceutical package comprising a pharmaceutical composition comprising one or more additional pharmaceutically acceptable minerals as pharmacologically active compounds for administration together or at different times, due to its obvious utility Provide what an effective improvement is achieved.

Furthermore, the present invention provides a pharmaceutical composition comprising epinastine or a pharmaceutically acceptable salt thereof as an active agent for the prevention and / or treatment of skin diseases, preferably skin diseases associated with allergic reactions, and A pharmaceutical package comprising a pharmaceutical composition comprising one or more additional pharmaceutically acceptable herbal medicines as pharmacologically active compounds for administration together or at different times, the obvious utility thereof To provide more effective improvements.
Furthermore, the present invention is highly effective in clearly improving the symptoms of itch, specifically urticaria, eczema, rash, dermatitis, rash, rash and psoriasis vulgaris associated with itching sensation. There is provided the use of said pharmaceutical composition in the manufacture of a medicament for the treatment of skin diseases by using a pharmaceutical compound.

Detailed Description of the Invention The present invention comprises an antihistamine effective amount of epinastine or a pharmaceutically acceptable salt thereof and one or more additional pharmaceutically acceptable minerals as pharmacologically active compounds. The present invention relates to a pharmaceutical composition, dosage form and package for the prevention and / or treatment of skin diseases.
Furthermore, the present invention provides an antihistaminic effective amount of epinastine or a pharmaceutically acceptable salt thereof and one or more additional pharmaceutically acceptable herbal medicines as pharmacologically active compounds for the treatment of skin diseases. It relates to pharmaceutical compositions, dosage forms and packages for prevention and / or treatment.

Epinastine, (±) 3-amino-9,13b-dihydro-1H-dibenz [c, f] imidazo [1,5-a] azepine, each of their hydrochlorides is a drug with H ₁ -antihistaminic properties is there. Primarily it has been used to treat allergic reactions of the eye and nasal mucosa.
The pharmaceutical composition, dosage form and package of the present invention may comprise salts such as hydrochloride, hydrobromide, oxalate, nitrate, sulfonate, fumarate, maleate, sulfate and phosphate or In the free base form, it contains epinastine. Preferred is epinastine hydrochloride.
The amount of epinastine or a pharmacologically acceptable salt thereof depends on the route of administration.

  For oral administration, the daily dose of epinastine or a pharmacologically acceptable salt thereof corresponding to adult epinastine hydrochloride depends on the severity and stage of the disease, the patient's weight and further parameters known to those skilled in the art. About 2-20 mg / day. The daily dose is preferably 5 to 15 mg, particularly preferably 7.5 to 12.5 mg. The daily dose can be administered once a day (e.g. 1 tablet per day) or divided into several times a day, e.g. 3 times a day (e.g. 3 tablets a day for 3 tablets). it can. Similarly, the amount of epinastine equivalent to epinastine hydrochloride or a pharmacologically acceptable salt thereof per dosage unit for oral administration (e.g. tablets or capsules) is 0.2-20 mg, preferably 0.5-15. Particularly preferred is 0.75 to 12.5 mg.

For topical administration, the amount corresponding to epinastine hydrochloride is 1-50 mg / g dosage form, preferably 2-30 mg / g dosage form, more preferably 5-15 mg / g dosage form.
In one embodiment of the invention, the pharmaceutical composition comprises an antihistamine effective amount of epinastine or a pharmaceutically acceptable salt thereof, and one or more additional pharmaceutically acceptable minerals. In the present invention, the mineral is a pharmaceutically acceptable compound containing one or more elements selected from the group consisting of calcium, zinc, iron, phosphorus, magnesium, potassium, copper, iodine, manganese, selenium, chromium and molybdenum. Means. One or more compounds of these minerals may be used to formulate the present invention.

Minerals used in the present invention include synthetic compounds, such as chemically synthesized compounds and enzymatically synthesized compounds, as well as natural products or their separated and purified forms.
There is no limitation on the form of mineral used in this aspect of the invention. Examples of forms include minerals, salts, oxides, protein complexes, protein split product complexes, polysaccharide complexes, polysaccharide split product complexes, modified starch complexes, Examples include dextrin complexes, metalloenzymes containing minerals such as superoxide dismutase, glutathione peroxidase and acid phosphatase, phosphoglucomutase metal active enzymes, enzymes containing metals outside the active center, or coenzymes.

  In this aspect of the invention, preferred minerals mean those selected from the group consisting of: calcium gluconate, calcium hydrogen phosphate, anhydrous dibasic calcium phosphate, calcium glycerophosphate, calcium lactate, precipitated calcium carbonate , Calcium chloride, calcium carbonate, calcium hydroxide, calcium citrate, calcium L-aspartate, calcium L-glutamate, calcium glycerophosphate, calcium 5'-ribonucleotide, calcium sulfate, tricalcium phosphate, calcium propionate, phosphate Calcium dihydrogen (monobasic calcium phosphate), calcium dihydrogen pyrophosphate, carboxymethylcellulose calcium, stearoyl-2-calcium lactate, calcium oxide, zinc sulfate, zinc gluconate, undecylenic acid Lead, zinc oxide, zinc carbonate, zinc chloride, zinc yeast, iron, iron sulfate, iron citrate, sodium iron citrate, iron gluconate, iron pyrophosphate (iron pyrophosphate [III]), iron succinate, iron chloride , Iron lactate, sugar-containing iron oxide, chondroitin sulfate sulfate / iron colloid, ammonium iron citrate, iron oxide red (iron trioxide), ferritin, heme iron, phosphoric acid, potassium dihydrogen phosphate, potassium monophosphate, phosphoric acid Dipotassium hydrogen, tripotassium phosphate, sodium diphosphate, sodium monophosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, trisodium phosphate, calcium diphosphate, tricalcium phosphate, calcium hydrogen phosphate, phosphorus Calcium dihydrogen, magnesium diphosphate, ammonium diphosphate, ammonium dihydrogen phosphate, diammonium hydrogen phosphate, pentaphosphate triphosphate Sodium, sodium polyphosphate, sodium hexametaphosphate, tetrapotassium pyrophosphate, disodium dihydrogen pyrophosphate, tetrasodium pyrophosphate, magnesium carbonate, magnesium sulfate, magnesium citrate, magnesium lactate, magnesium chloride, magnesium oxide, aluminum silicate Magnesium, magnesium aluminate metasilicate, magnesium aluminum hydroxide, magnesium L-aspartate, magnesium L-glutamate, potassium chloride, potassium sulfate, potassium carbonate, potassium dihydrogen citrate, tripotassium citrate, potassium gluconate, potassium acetate , Tripotassium phosphate, dipotassium hydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium hydroxide, potassium aluminum sulfate, potassium L-aspartate Monopotassium L-glutamate, copper sulfate, copper gluconate, copper chlorophyllin sodium, copper yeast, iodine, potassium iodide, sodium iodide, iodolecithin, magnesium chloride, magnesium sulfate, magnesium yeast, sodium selenide, selenium disulfide, Selenocysteine, selenomethionine, selenium yeast, chromium chloride, chromium yeast, sodium molybdate, molybdenum yeast.

In addition, the compositions of this aspect of the present invention include other pharmacologically active compositions such as antihistamines other than epinastine, such as diphenhydramine, chloropheniramine, carbinoxamine, diphenylpyralin and promethazine, anti-inflammatory agents such as glycyrrhizic acid ( Glycyrrhizin), dipotassium glycyrrhizinate, potassium glycyrrhizinate, monoammonium glycyrrhizinate, diammonium glycyrrhizinate, glycyrrhetinic acid, and tranexamic acid, vitamin B group and vitamin-like active substances such as vitamin B ₁ , vitamin B ₆ , vitamin B ₁₂ , Niacin, pantothenic acid, biotin, folic acid, orotic acid, lipoic acid, p-aminobenzoic acid, inositol, carnitine and choline, antioxidant vitamins and antioxidant vitamin-like substances such as vitamin C, vitamin Emissions E, vitamin A, ubiquinone, pangamic acid, and flavonoids, sulfur-containing amino acids such as cysteine, methionine, aminoethyl sulfate and glutathione and vitamin D group, e.g. ergocalciferol and cholecalciferol shea phenol.

The amount of mineral to be formulated in this embodiment of the invention varies with the type of mineral used, but the daily oral dosage for adults is about 0.3 μg to 4000 mg, topical about 0.1 mg / g to 800 mg / day. g.
More specifically, the combined amount of each mineral for incorporation in this aspect of the invention is as follows per adult day:
The combination amount of calcium as a calcium-containing mineral is preferably 2500 mg or less, more preferably 10 mg to 600 mg, and most preferably 30 mg to 300 mg.
The combination amount of zinc as the zinc-containing mineral is preferably 30 mg or less, more preferably 0.02 mg to 24 mg, and most preferably 0.12 mg to 12 mg.

The combination amount of iron as an iron-containing mineral is preferably 40 mg or less, more preferably 0.01 mg to 20 mg, and most preferably 0.1 mg to 10 mg.
The combination amount of phosphorus as a phosphorus-containing mineral is preferably 4000 mg or less, more preferably 1 mg to 2000 mg, and most preferably 7 mg to 700 mg.
The combination amount of magnesium as the magnesium-containing mineral is preferably 700 mg or less, more preferably 1 mg to 640 mg, and most preferably 3.2 mg to 320 mg.
The combination amount of potassium as the potassium-containing mineral is preferably 4000 mg or less, more preferably 1 mg to 3000 mg, and most preferably 2 mg to 2000 mg.
The combination amount of copper as the copper-containing mineral is preferably 9 mg or less, more preferably 0.001 mg to 3.6 mg, and most preferably 0.01 mg to 1.8 mg.

The combination amount of iodine as an iodine-containing mineral is preferably 3 mg or less, more preferably 10 μg to 1000 μg, and most preferably 1.5 μg to 150 μg.
The combination amount of manganese as a manganese-containing mineral is preferably 20 mg or less, more preferably 0.01 mg to 10 mg, and most preferably 0.04 mg to 4 mg.
The combination amount of selenium as a selenium-containing mineral is preferably 250 μg, more preferably 0.01 μg to 150 μg, and most preferably 0.5 μg to 55 μg.
The combination amount of chromium as the chromium-containing mineral is preferably 250 μg or less, more preferably 0.01 to 150 μg, and most preferably 0.3 μg to 35 μg.

The combination amount of molybdenum as the molybdenum-containing mineral is preferably 250 μg or less, more preferably 0.01 μg to 150 μg, and most preferably 0.3 μg to 30 μg.
Further, for topical use, the combination amount as a mineral is 800 mg / g or less, more preferably 0.1 mg / g to 500 mg / g, most preferably 0.45 mg / g to 450 mg / g per composition.
Particularly preferred examples of oral minerals are those containing calcium. It is preferable to use one or more calcium containing minerals selected from calcium gluconate, calcium hydrogen phosphate, anhydrous dibasic calcium phosphate, calcium glycerophosphate, calcium lactate and / or precipitated calcium carbonate. The amount of calcium for formulating the present invention is preferably 30 mg to 300 mg per adult day.

Particularly preferred examples of topical minerals include zinc. It is particularly preferred to use one or more zinc containing minerals selected from zinc oxide and / or zinc undecylenate. Zinc oxide may be used as zinc oxide starch powder. The amount of zinc is preferably 0.45 mg / g to 450 mg / g per composition.
The pharmaceutical composition described in this aspect of the invention may be given orally in a single dose or in divided doses and may be topically applied directly to the affected area of the skin in a single dose or in divided doses. Also good. Adjustment of the amount of epinastine and minerals may reflect age, weight and emerging symptoms.
In a further aspect, the present invention provides an immediate release of epinastine or a pharmaceutically acceptable salt thereof and also provides a sustained release of all or part of one or more pharmaceutically acceptable minerals. And to an oral pharmaceutical composition.

Furthermore, if the pharmaceutical composition described in this aspect of the present invention is administered orally, some or all of the mineral used as the sustained release component may be replaced with epinastine (or epinastine and one of the immediate release components). Part mineral). When further active ingredients are combined, the further active ingredients may be divided into sustained release or immediate release ingredients according to the pharmacokinetic properties of each active ingredient.
These immediate release component and sustained release component may be manufactured separately as different formulations, or manufactured as a single formulation and then packaged together in each dosage unit. For example, the quick-release tablet and the sustained-release tablet are packaged in one package, or the quick-release tablet and the sustained-release capsule are packaged in one package. Single preparations include, for example, multi-layer tablets with a combination of immediate-release and sustained-release layers, immediate-release granules and sustained-release granules, or granules with capsules filled with such granules, small immediate-release tablets and small sustained-release tablets. Examples include hard capsules filled with a combination for release, and dry syrup or suspension syrup using microcapsules or microspheres as sustained-release components.

Such multi-layer tablets (eg, bilayer tablets, also called bilayer tablets) are sustained release and epinastine or pharmaceutically acceptable of all or part of one or more pharmaceutically acceptable minerals. An immediate release of those salts can be provided.
Such a bilayer tablet comprises a first layer A which provides an immediate release of epinastine comprising epinastine or a pharmaceutically acceptable salt thereof and optionally a part of a pharmaceutically acceptable mineral, and 1 or 2 A second layer B may be included that provides a sustained release of one or more minerals including all or part of the above pharmaceutically acceptable minerals. The bilayer tablet may further comprise a tablet coating consisting of a pharmaceutically acceptable excipient. Each layer of the bilayer tablet is in contact with each other on a portion of their surface, but provides an independent release profile of both active substances.

  In other aspects of the invention, the pharmaceutical composition comprises an antihistamine effective amount of epinastine or a pharmaceutically acceptable salt thereof, and one or more additional pharmaceutically acceptable herbal medicines. Examples of herbal medicines used in the present invention include Artemisiae capillari flos, Ginseniae fructus, Daihyo Rhei rhizoma, Saiko (Bupleuri radix), Hamabou Glehniae radix cum rhizoma), salmon (Pork), cherry bark (Pruni jamasakura bark), bellflower (Platycodi radix), ginger (Zingiberis rhizoma), salmon (Araliae cardatae rhizoma), salmon (Kaigai Schizonepetae spica) Licorice Glycyrrhizae radix), well-known (Coicis semen), mountain return (Smilacis rhizoma), religion (Forsythiae fructus), religion grass (Glenchomae herba), red magoliae flosiz, river cuid Is mentioned. One or more of these herbal medicines may be used to formulate the present invention. Furthermore, these herbal medicines can be made into dry powder, extract, fluid extract, tincture, oil and the like.

In addition, the compositions of this aspect of the invention include other pharmacologically active compositions such as pharmaceutically acceptable minerals such as calcium, zinc, iron, phosphorus, magnesium, potassium, copper, iodine, manganese Selenium, chromium and molybdenum-containing minerals, antihistamines other than epinastine, such as diphenhydramine, chlorpheniramine, carbinoxamine, diphenylpyraline and promethazine, anti-inflammatory agents such as glycyrrhizic acid (glycyrrhizinate), dipotassium glycyrrhizinate, potassium glycyrrhizinate, glycyrrhizic acid monoammonium, glycyrrhizinate diammonium, glycyrrhetinic acid and tranexamic acid, B vitamins and vitamin-like active substances, such as vitamins B _1, vitamin B _6, vitamin B _12, niacin, punt Acids, biotin, folic acid, orotic acid, lipoic acid, p-aminobenzoic acid, inositol, carnitine and choline, antioxidant vitamins and antioxidant vitamin-like substances such as vitamin C, vitamin E, vitamin A, ubiquinone, pangamic acid, And flavonoids, sulfur-containing amino acids such as cysteine, methionine, aminoethylsulfonic acid and glutathione and vitamin D groups such as ergocalciferol and cholecalciferol.

The combination amount of pharmaceutically acceptable crude drugs for formulating the present invention varies depending on the type of crude drug used, but the oral dose per day for adults is about 5 mg to about 30000 mg as a crude drug substance, Is about 0.1 mg / g to 800 mg / g as a crude drug substance.
As a further detail, the combined amount of each herbal medicine for oral use to formulate the present invention as an adult daily dose is as follows:
The combination amount of herbal medicines, such as 茵陳 茵, ginger, licorice and often 苡 nin, is preferably 30000 mg or less, more preferably 15 mg to 20000 mg, most preferably 30 mg to 10000 mg as a herbal substance.
The amount of combination of herbal medicines, for example, mountain lion, Daihuang, Saiko, Hama wind, 茯苓, 羌活, 荊芥, Yamakagei, and Rengen grass is preferably 10000 mg or less, more preferably 10 mg to 7500 mg, most preferably 20 mg to 5000 mg as a herbal substance. It is.

The amount of combination of crude drugs such as cherry bark, bellflower and ream is 5,000 mg or less, more preferably 5 mg to 4000 mg, most preferably 10 mg to 2500 mg as a crude drug substance.
Further, for topical use, the amount of combination as a crude drug is 0.1 mg / g to 800 mg / g, more preferably 0.1 mg / g to 500 mg / g, most preferably 0.45 mg / g to 450 mg / g as a crude drug substance. is there.
The pharmaceutical composition of this aspect of the invention may be topically applied once or orally in divided doses and directly to the affected area of the skin once or in divided doses. Adjustments to the amount of epinastine and herbal medicine may reflect age, weight and emerging symptoms.
In a further aspect, the present invention provides an oral pharmaceutical composition that provides immediate release of epinastine or a pharmaceutically acceptable salt thereof and sustained release of all or a portion of one or more pharmaceutically acceptable herbal medicines. Related to things.

Further, when orally administering the pharmaceutical composition of this aspect of the present invention, a part or all of the herbal medicine used as the sustained-release ingredient is combined with the immediate-release ingredient of epinastine (or part of epinastine and herbal medicine). May be. When further active ingredients are combined, the further active ingredient may be divided into sustained release or immediate release ingredients according to the pharmacokinetic properties of each active ingredient.
These immediate-release component and sustained-release component may be produced separately as different preparations or may be produced as a single preparation and then packaged together in each dosage unit. For example, the quick release tablet and the sustained release tablet are packaged in one package, or the quick release tablet and the sustained release capsule are packaged in one package. As a single preparation, for example, a multilayer tablet containing an immediate release layer and a sustained release layer, a granule comprising a combination of immediate release granules and sustained release granules, or a capsule filled with such granules, a small immediate release tablet And hard capsules filled with a combination of small sustained-release tablets, and dry syrup or suspension syrup using microcapsules or microspheres as sustained-release components.

The pharmaceutical composition described in the present invention is in an oral form, such as tablets, granules, microparticles, powders, capsules, caplets, soft capsules, pills, suspensions, emulsions, oral solutions, syrups, dry syrups, chewable forms, effervescent tablets, Can be used in drop and oral fast-dispersing tablets and topical forms such as creams, ointments, gel ointments, suppositories, poultices, tapes, topical solutions, aerosols, lotions and foams . Furthermore, preparations formed into microparticles such as microcapsules, nanocapsules, microspheres, nanospheres, liposomes may be included in the composition.
Such multi-layered tablets (eg, bilayer tablets, also referred to as bilayer tablets) are sustained release and epinastine or pharmaceutically acceptable of all or part of one or more pharmaceutically acceptable herbal medicines. An immediate release of these salts may be provided.

Such a bilayer tablet comprises a first layer A providing an immediate release of epinastine comprising epinastine or a pharmaceutically acceptable salt thereof and optionally a part of a pharmaceutically acceptable herbal medicine, and 1 or 2 A second layer B may be included that provides for the sustained release of one or more herbal medicines including all or part of the above pharmaceutically acceptable herbal medicines. The bilayer tablet may further comprise a tablet coating consisting of a pharmaceutically acceptable excipient. Each layer of the bilayer tablet is in contact with each other on a portion of their surface, but provides an independent release profile of both active substances.
In addition, the properties of the composition of the present invention, such as stability, release, persistence, disintegration, distinglation, solubility, taste masking, improved usage, etc., in the art. It can be adjusted by adding known additives.

  For example, the pharmaceutically active substance can be distributed into separate granules, multilayer granules, multilayer tablets or dry-coated tablets, separate granule tablets, microcapsules and the like. Along with coated preparations such as sugar-coated tablets, film-coated tablets, coated granules, and effervescent tablets or effervescent granules, as well as comminutions, solid solutions and the like, mention may be made of oral dissolution preparations and chewable preparations in matrix preparations. Sweetening agents, refrigerants, antioxidants or stabilizers, agents that adjust certain pH values and agents that affect viscosity, osmotic pressure or salt concentration can be added. These methods can be combined.

  If desired, the following additives can be added: excipients, bases, binders, disintegrants, lubricants, superplastic materials, coatings, dragees, plasticizers, antifoams, brighteners, Foaming agent, antistatic agent, drying agent, humidifier, surfactant, solubilizer, buffer, solvent, solubilizer, solvent, diluent, stabilizer, emulsifier, suspension, suspending agent, dispersing agent, etc. Tonicity agent, aerosol propellant, adsorbent, reducing agent, antioxidant, base, wetting agent, wetting modifier, filler, extender, adhesive, adhesive, softener, pH modifier, antiseptic Agents, preservatives, sweeteners, flavoring agents, cooling agents, flavoring agents, fragrances, fragrances, coloring materials and the like. These additives may be used in a normal production method, but the production method is not limited.

Examples of these additives are described in Japanese Pharmaceutical Excipients Directory 2000 (Japan Pharmaceutical Additives Association Edition, published by the Pharmaceutical Affairs Daily).
These preparations can be produced in a conventional manner, for example, by adding a preparation additive to a pharmacologically active substance.
The compositions described in the present invention are illustrated by the following examples. However, the pharmaceutical composition of the present invention is not limited by these examples.

Example 1
: Tablet The following ingredients were mixed uniformly. The obtained mixed particles were compressed in a mold to produce tablets of 300 mg each.
Epinastine hydrochloride 10g
900g calcium gluconate
Pyridoxine hydrochloride 22g
Lactose 200g
Microcrystalline cellulose 636g
Light anhydrous silicic acid 15g
Magnesium stearate 12g
Talc 5g

Example 2
: Powder The following components were mixed uniformly. The obtained mixed particles were divided into 600 mg units to produce a powder composition.
Epinastine hydrochloride 5g
Calcium hydrogen phosphate 540g
363g calcium lactate
Cornstarch 258g
Lactose 260g
Magnesium stearate 12g

Example 3
: Two-layer tablet
The following ingredients of layer A and layer B were processed by conventional methods to provide mixed particles, respectively, and the particles were compressed to form 300 mg bilayer tablets (A layer 60 mg, B layer 240 mg), respectively.
A layer epinastine hydrochloride 50g
Lactose 266g
Microcrystalline cellulose 272g
Light anhydrous silicic acid 6g
Talc 3g
Magnesium stearate 3g
Layer B calcium glycerophosphate 1200g
Dipotassium glycyrrhizinate 300g
60g pyridoxine hydrochloride
Lactose 700g
Hardened oil 50g
Hydroxypropyl methylcellulose 2208 80g
Magnesium stearate 10g

Example 4
: Internal solution The following components were dissolved in sterilized purified water, adjusted to pH 5 by adding sodium hydride, and diluted with sterilized purified water to obtain a total volume of 20 L. The obtained solution was transferred to a glass bottle every 50 mL to provide a liquid for internal use.
Epinastine hydrochloride 4g
Calcium gluconate 400g
Potassium L-aspartate 40g
Magnesium L-aspartate 40g
1.2g ammonium iron (III) citrate
Glycyrrhizic acid 40g
Aminoethylsulfonic acid 80g
Riboflavin sodium phosphate 1.2g
10g pyridoxine hydrochloride
Nicotinamide 10g
Citric acid 50g
Sodium citrate 10g
Purified sucrose 2400g
Caramel 60g
Sodium hydroxide Appropriate amount Preservative Appropriate amount Flavor Small amount Sterilized purified water Appropriate amount

Example 5
: Sugar-coated tablets The following ingredients were processed by conventional methods to provide mixed particles, which were compressed to form 240 mg tablets each.
Epinastine hydrochloride 10g
Calcium hydrogen phosphate 250g
Dipotassium glycyrrhizinate 200g
Pyridoxine hydrochloride 50g
Riboflavin butyrate 12g
Lactose 640g
Corn starch 406g
Microcrystalline cellulose 306g
Low substituted hydroxypropylcellulose 130g
Hydroxypropylcellulose 90g
Light anhydrous silicic acid 45g
Talc 12g
Magnesium stearate 9g

  The tablets were then transferred to a coating pan and coated using a coating solution. A mixture of equal amounts of ethyl alcohol and purified water containing 5% by mass / volume hydroxypropyl methylcellulose increased by 10 mg / dose per tablet. Next, the tablets are prepared using an aqueous solution containing 2 mass / volume percent talc, 2 mass / volume percent titanium oxide, 3 mass / volume percent calcium carbonate, 1 mass / volume percent powdered acacia, and 60 mass / volume percent purified sucrose. Coated and increased by 150 mg mass / volume per tablet. Finally, the tablets were coated with an aqueous solution containing 60% mass / volume purified sucrose, increasing by 30 mg mass / volume per tablet. In this way, sugar-coated tablets were produced.

Example 6
: Cream The following ingredients were processed by a usual method to form a total amount of 1 kg of cream, and adjusted to pH 5 by adding sodium citrate.
Epinastine hydrochloride 10.0g
Zinc undecylenate 30.0g
Glycyrrhetinic acid 10.0g
Pyridoxine hydrochloride 1.0g
Medium chain fatty acid triglyceride 200.0g
Propylene glycol 150.0g
Glyceryl monostearate 80.0g
Polyoxyethylene cetyl ether 40.0g
Diisopropyl adipate 50.0g
Citric acid 0.1g
Sodium citrate Suitable amount Preservative Suitable amount Purified water Suitable amount

Example 7
: Ointment The following ingredients were processed in the usual manner to form a total amount of 1 kg ointment.
Epinastine hydrochloride 10g
Zinc oxide 100g
40 g paraffin
Cetanol 30g
30g white wax
Preservative appropriate amount White petrolatum appropriate amount

Example 8
: Tablet The following ingredients were mixed uniformly. The obtained mixed particles were molded and compressed to produce tablets of 250 mg each.
Epinastine hydrochloride 10g
Yangcheng Hot Spring Extract
(2 kg of Chen Chen, 1.5 kg of mountain lion, 0.5 kg of big yellow) 400 g
dl-methylephedrine hydrochloride 90g
Lactose 345g
Microcrystalline cellulose 375g
Light anhydrous silicic acid 5g
Talc 5g
Magnesium stearate 5g

Example 9
: Powder The following components were mixed uniformly. The obtained mixed particles were divided into 800 mg units to produce a powder composition.
Epinastine hydrochloride 10g
Saiko 90g
90g beach wind
90g powder
Cherry bark 90g
90g of bellflower
Ginger powder 90g
90g
54g powder
Licorice powder 54g
Well 54g
Cornstarch 648g
Lactose 660g
Magnesium stearate 20g

Example 10
: Granules The following ingredients were produced as granules by the usual method, mixed particles were produced and filled to give 1500 mg of granules per pack.
Epinastine hydrochloride 20g
Licorice extract 100g
(Licorice 400g)
30g thiamine nitrate
Riboflavin 24g
90g pyridoxine hydrochloride
Nicotinamide 300g
Calcium pantothenate 60g
Calcium ascorbate 360g
Carboxymethylcellulose calcium 200g
Mannitol 1260g
Cornstarch 515g
Aspartame 20g
Acesulfame potassium 20g
Aromatic material 1g

Example 11
: Film-coated tablets The following ingredients were processed by conventional methods to provide mixed particles, which were compressed to form 200 mg tablets each.
Epinastine hydrochloride 20g
Large yellow powder 800g
100g mountain return
100g
100g of recurring grass
Lactose 656g
600g microcrystalline cellulose
Light anhydrous silicic acid 12g
Talc 6g
Magnesium stearate 6g

  The tablets were then transferred to a coating pan and coated using a coating solution. From an equal mixture of ethyl alcohol and purified water containing 5% by mass / hydroxypropyl methylcellulose, the amount was increased by 10 mg / dose per tablet. Film-coated tablets were thus produced.

Example 12
: Oral solution The following components were dissolved in sterilized purified water, sodium hydride was added to adjust to pH 5, diluted with sterilized purified water to a total volume of 20 L. The resulting solution was transferred in 50 ml increments to a glass bottle to provide an oral solution.
Epinastine hydrochloride 4g
Sakura bark extract (800g cherry bark) 800mL
Soryu extract 120mL
(茯苓 120g)
Kikyo flow extract
(Kikyo 240g) 240mL
Well 苡 nin style extract
(Well well 240g) 240mL
Ascorbic acid 40g
Aminoethylsulfonic acid 400g
Citric acid 50g
Sodium citrate 10g
Purified sucrose 2400g
Caramel 60g
Sodium hydroxide Appropriate amount Preservative Appropriate amount Flavor Small amount Sterilized purified water Appropriate amount

Example 13
: Ointment The following ingredients were processed in the usual manner to form a total amount of 1 kg ointment.
Epinastine hydrochloride 10g
2g
Glycyrrhetinic acid 10g
Crotamiton 20g
Lidocaine 20g
40 g paraffin
Cetanol 30g
30g white wax
Preservative appropriate amount White petrolatum appropriate amount

Claims (31)

a) epinastine or a pharmaceutically acceptable salt thereof, and
b1) One or more additional pharmaceutically acceptable substances containing one or more elements selected from the group consisting of calcium, zinc, iron, phosphorus, magnesium, potassium, copper, iodine, manganese, selenium, chromium and molybdenum Minerals that can be
b2) A pharmaceutical composition for the treatment of skin diseases comprising one or more additional pharmaceutically acceptable herbal medicines. a) epinastine or a pharmaceutically acceptable salt thereof, and
b1) One or more additional pharmaceutically acceptable substances containing one or more elements selected from the group consisting of calcium, zinc, iron, phosphorus, magnesium, potassium, copper, iodine, manganese, selenium, chromium and molybdenum The pharmaceutical composition for the treatment of skin diseases according to claim 1, comprising a mineral that can be treated.   Mineral is calcium gluconate, calcium hydrogen phosphate, anhydrous dibasic calcium phosphate, calcium glycerophosphate, calcium lactate, precipitated calcium carbonate, calcium chloride, calcium carbonate, calcium hydroxide, calcium citrate, calcium L-aspartate, L -Calcium glutamate, calcium glycerophosphate, calcium 5'-ribonucleotide, calcium sulfate, tricalcium phosphate, calcium propionate, calcium dihydrogen phosphate (monobasic calcium phosphate), dihydrogen pyrophosphate, carboxymethylcellulose calcium, stearoyl -2-Calcium lactate, calcium oxide, zinc sulfate, zinc gluconate, zinc undecylenate, zinc oxide, zinc carbonate, zinc chloride, zinc yeast, iron, iron sulfate, iron citrate, iron citrate Lithium, iron gluconate, iron pyrophosphate (iron pyrophosphate [III]), iron succinate, iron chloride, iron lactate, sugar-containing iron oxide, chondroitin sulfate / iron colloid, ammonium iron citrate, red iron oxide (trioxide dioxide Iron), ferritin, heme iron, phosphoric acid, potassium dihydrogen phosphate, potassium monophosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium diphosphate, sodium monophosphate, disodium hydrogen phosphate, phosphorus Sodium dihydrogen phosphate, trisodium phosphate, calcium diphosphate, tricalcium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, magnesium diphosphate, ammonium diphosphate, ammonium dihydrogen phosphate, diammonium hydrogen phosphate , Pentapotassium triphosphate, sodium polyphosphate, sodium hexametaphosphate, tetrapotassium pyrophosphate, pylori Disodium dihydrogen acid, tetrasodium pyrophosphate, magnesium carbonate, magnesium sulfate, magnesium citrate, magnesium lactate, magnesium chloride, magnesium oxide, magnesium aluminum silicate, magnesium aluminate metasilicate, magnesium aluminum hydroxide, L-aspartic acid Magnesium, magnesium L-glutamate, potassium chloride, potassium sulfate, potassium carbonate, potassium dihydrogen citrate, tripotassium citrate, potassium gluconate, potassium acetate, tripotassium phosphate, dipotassium hydrogen phosphate, dipotassium hydrogen phosphate , Potassium dihydrogen phosphate, potassium hydroxide, potassium aluminum sulfate, potassium L-aspartate, monopotassium L-glutamate, copper sulfate, copper gluconate, copper chlorophyllin sodium, copper yeast , Iodine, potassium iodide, sodium iodide, iodolecithin, magnesium chloride, magnesium sulfate, magnesium yeast, sodium selenide, selenium disulfide, selenocysteine, selenomethionine, selenium yeast, chromium chloride, chromium yeast, sodium molybdate, The pharmaceutical composition according to claim 2, which is selected from the group consisting of molybdenum yeasts.   The pharmaceutical composition according to claim 2 or 3, wherein the composition is for oral use, and the amount of epinastine or pharmaceutically acceptable salt thereof per day for adults is 2 to 20 mg corresponding to epinastine hydrochloride. .   The pharmaceutical composition according to any one of claims 2 to 4, wherein the composition is for oral use and the amount of pharmaceutically acceptable mineral is 0.3 µg to 4000 mg.   The pharmaceutical composition according to any one of claims 2 to 5, wherein the pharmaceutically acceptable mineral comprises calcium.   The pharmaceutical composition according to claim 6, wherein the calcium-containing mineral is selected from the group consisting of calcium gluconate, calcium hydrogen phosphate, dibasic calcium phosphate phosphate, calcium glycerophosphate, calcium lactate, and precipitated calcium carbonate.   The pharmaceutical composition according to any one of claims 2 to 7, wherein the amount of calcium per day for an adult is 30 mg to 300 mg.   9. An oral pharmaceutical composition according to any one of claims 2 to 8, which provides an immediate release of epinastine or a pharmaceutically acceptable salt thereof and a sustained release of all or part of one or more minerals. object.   The composition according to claim 2 or 3, wherein the composition is topical and the amount of epinastine or a pharmaceutically acceptable salt thereof is 1 to 50 mg as equivalent to epinastine hydrochloride per gram of the composition. Pharmaceutical composition.   11. The pharmaceutical composition according to any one of claims 2, 3 or 10, wherein the composition is topical and the amount of pharmaceutically acceptable mineral is from 0.1 to 800 mg / g composition.   12. The pharmaceutical composition according to any one of claims 2, 3, 10 or 11, wherein the pharmaceutically acceptable mineral comprises zinc.   The pharmaceutical composition according to claim 12, wherein the zinc-containing mineral is selected from the group consisting of zinc oxide and zinc undecylenate.   The pharmaceutical composition according to any one of claims 2, 3, and 10 to 14, wherein the amount of zinc is 0.45 mg / g to 450 mg / g composition.   Pharmaceutical compositions comprising epinastine or a pharmaceutically acceptable salt thereof as an active agent, and pharmacologically active agents for administration together or time-shifted include calcium, zinc, iron, phosphorus, magnesium, potassium, A pharmaceutical package comprising a pharmaceutical composition comprising one or more pharmaceutically acceptable minerals comprising one or more elements selected from the group consisting of copper, iodine, manganese, selenium, chromium and molybdenum.   Mineral is calcium gluconate, calcium hydrogen phosphate, anhydrous dibasic calcium phosphate, calcium glycerophosphate, calcium lactate, precipitated calcium carbonate, calcium chloride, calcium carbonate, calcium hydroxide, calcium citrate, calcium L-aspartate, L -Calcium glutamate, calcium glycerophosphate, calcium 5'-ribonucleotide, calcium sulfate, tricalcium phosphate, calcium propionate, calcium dihydrogen phosphate (monobasic calcium phosphate), dihydrogen pyrophosphate, carboxymethylcellulose calcium, stearoyl -2-Calcium lactate, calcium oxide, zinc sulfate, zinc gluconate, zinc undecylenate, zinc oxide, zinc carbonate, zinc chloride, zinc yeast, iron, iron sulfate, iron citrate, iron citrate Lithium, iron gluconate, iron pyrophosphate (iron pyrophosphate [III]), iron succinate, iron chloride, iron lactate, sugar-containing iron oxide, chondroitin sulfate / iron colloid, ammonium iron citrate, red iron oxide (trioxide dioxide Iron), ferritin, heme iron, phosphoric acid, potassium dihydrogen phosphate, potassium monophosphate, dipotassium hydrogen phosphate, tripotassium phosphate, sodium diphosphate, sodium monophosphate, disodium hydrogen phosphate, phosphorus Sodium dihydrogen phosphate, trisodium phosphate, calcium diphosphate, tricalcium phosphate, calcium hydrogen phosphate, calcium dihydrogen phosphate, magnesium diphosphate, ammonium diphosphate, ammonium dihydrogen phosphate, diammonium hydrogen phosphate , Pentapotassium triphosphate, sodium polyphosphate, sodium hexametaphosphate, tetrapotassium pyrophosphate, pylori Disodium dihydrogen acid, tetrasodium pyrophosphate, magnesium carbonate, magnesium sulfate, magnesium citrate, magnesium lactate, magnesium chloride, magnesium oxide, magnesium aluminum silicate, magnesium aluminate metasilicate, magnesium aluminum hydroxide, L-aspartic acid Magnesium, magnesium L-glutamate, potassium chloride, potassium sulfate, potassium carbonate, potassium dihydrogen citrate, tripotassium citrate, potassium gluconate, potassium acetate, tripotassium phosphate, dipotassium hydrogen phosphate, dipotassium hydrogen phosphate , Potassium dihydrogen phosphate, potassium hydroxide, potassium aluminum sulfate, potassium L-aspartate, monopotassium L-glutamate, copper sulfate, copper gluconate, copper chlorophyllin sodium, copper yeast , Iodine, potassium iodide, sodium iodide, iodolecithin, magnesium chloride, magnesium sulfate, magnesium yeast, sodium selenide, selenium disulfide, selenocysteine, selenomethionine, selenium yeast, chromium chloride, chromium yeast, sodium molybdate, 16. The pharmaceutical package according to claim 15, selected from the group consisting of molybdenum yeasts.   Use of the pharmaceutical composition or package according to any one of claims 1 to 16 for the manufacture of a medicament for the treatment and / or prevention of skin diseases.   18. Use according to claim 17, wherein the skin disease is associated with an allergic reaction.   Use according to claim 17 or 18, wherein the skin disease is urticaria, eczema, skin irritation, dermatitis, pruritus, urticaria and psoriasis vulgaris. a) epinastine or a pharmaceutically acceptable salt thereof, and
b) A pharmaceutical composition according to claim 1 for the treatment of skin diseases, comprising one or more additional pharmaceutically acceptable herbal medicines.   The pharmaceutically acceptable herbal medicines are: Chen Chen Wei, Mountain Lion, Daihuang, Saiko, Hamafu, Aoi, Cherry Bark, Kikyo, Ginger, Sakai, Bamboo, Licorice, Well, Jinjin, Yamagai, Renren, Renjigra, 21. The pharmaceutical composition according to claim 20, which is selected from the group consisting of river cucumbers.   The pharmaceutical composition according to claim 20 or 21, wherein the composition is for oral use, and the amount of epinastine or pharmaceutically acceptable salt thereof per day for adults is 2 to 20 mg corresponding to epinastine hydrochloride. .   23. The pharmaceutical composition according to any one of claims 20 to 22, wherein the composition is for oral use and the daily dose of the crude drug is 5 mg to 30000 mg of the crude drug substance.   24. An oral medicament according to any one of claims 20 to 23, which provides immediate release of epinastine or a pharmaceutically acceptable salt thereof and sustained release of all or part of one or more herbal medicines. Composition.   The pharmaceutical composition according to claim 20 or 21, wherein the composition is topical and the amount of epinastine or a pharmaceutically acceptable salt thereof is 1 to 50 mg as equivalent to epinastine hydrochloride per gram of the composition. Composition.   26. The pharmaceutical composition for the treatment of skin diseases according to any one of claims 20, 21 and 25, wherein the composition is topical and the amount of crude drug is 0.1-800 mg of crude drug substance per gram of composition.   A pharmaceutical composition comprising epinastine or a pharmaceutically acceptable salt thereof as an active agent, and one or more pharmaceutically acceptable crude drugs as a pharmacologically active agent for administration together or time-shifted A pharmaceutical package comprising a pharmaceutical composition comprising.   Herbal medicine consists of 茵 茵 蒿, 梔 梔, 黄黄, 浜, 防, 皮, cherry bark, bellflower, ginger, 羌活, 荊芥, licorice, well 苡 nin, mountain return, liaison, ream grass, spicy and / or river cucumber. 28. A pharmaceutical package according to claim 27, selected from the group.   Use of the pharmaceutical composition or package according to any one of claims 20 to 28 for the manufacture of a medicament for the treatment and / or prevention of skin diseases.   30. Use according to claim 29, wherein the skin disease is associated with an allergic reaction.   Use according to claim 29 or 30, wherein the skin disease is urticaria, eczema and skin irritation, dermatitis, pruritus, urticaria and psoriasis vulgaris.