The local drug application for immunosuppression and treatment of autoimmune or allergic diseases

 

(57) Abstract:

Serves the local drug application for inhibiting the rejection of organ or bone marrow transplantation or for the treatment of autoimmune or allergic diseases, as activitiesthese connection contains 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol or its pharmaceutically acceptable acid additive salt. 7 C.p. f-crystals, 1 table.

The invention relates to an external preparation for topical application, in particular to the outer local drug use, containing as activitiesthese substance 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol or its pharmaceutically acceptable acid additive salt.

In WO 94/08943 disclosed 2-aminopropan-1,3-dialogue compounds that can be used as immunosuppressants. In the study of these compounds, it was found that this compound, as the hydrochloride of 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol (hereinafter referred to as Compound (1)) can be used for organ transplantation and for the treatment of autoimmune diseases. To suppress rejection of organ or bone tissue and for the treatment of auto the military sites in combination with oral administration. However, it is desirable to develop such pharmaceutical Compounds (1), which could be introduced through the skin, eyes, lungs, bronchi, nasal cavity or rectum.

The aim of the invention is to develop a pharmaceutical product of the Compound (1), which could be introduced through the skin, eyes, lungs, bronchi, nasal cavity or rectum.

Thus, the present invention relates to an external preparation for local application, which as activitiesthese substance contains 2-amino-2-(2-(4-octylphenyl))ethyl)propane-1,3-diol or its pharmaceutically acceptable acid additive salt.

The connection according to the invention can be obtained by methods described in WO 94/08943.

Pharmaceutically acceptable acid additive salts are salts formed with inorganic acids such as hydrochloride, Hydrobromic, or sulfate; or salts formed with organic acids such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate or benzoylphenyl, while preferred is the hydrochloride. In the scope of the present invention also includes a hydrate or MES connection of infusion of the receiving connection of the present invention, may be in the form of an ointment, paste, liniment (liquid ointment, lotion, plaster, poultice, eye drops, eye ointment, suppository, means to compress, inhalant, spray, aerosol, viscous medicinal substances, applied with a brush, nose drops, creams, adhesive tape, swab, etc.

The preparation contains the compound according to the invention in the form of a mixture with an organic or inorganic carrier or excipient, and may be, for example, used in the form of solid, semi-solid or liquid medicines.

The connection according to the invention can be mixed, for example, non-toxic and pharmaceutically acceptable carrier, which is typically used for obtaining a drug intended for local use.

As the carrier can be used are water, glucose, lactose, Arabian gum, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal krasnozem, potato starch, urea and other carriers that are suitable for the manufacture of solid, semi-solid or liquid compositions. In these compositions may, in addition, added adjuvant.

The number of joint the ve active ingredient, should be sufficient to give the drug to the desired activity and depends on the symptoms or the severity of the disease. In the case of treatment of symptoms and diseases caused by immune disorders, mentioned below, the connection according to the invention can be used in the form of standardized pharmaceutical compositions for topical application, aerosol composition or compositions for rectal administration, containing and non-toxic pharmaceutically acceptable carrier, adjuvant or excipient. In the case of treatment of reversible airway obstruction compound of the present invention, it is preferable to introduce into the lungs in the form of an aerosol of the drug manufactured, in particular, in the form of powder or solution.

The number of compounds according to the invention, which can be mixed with a carrier depends on the particular individual undergoing treatment, and specifically selected dosage forms. The specific dose for the introduction of an individual patient should be determined based on many factors, such as age, body weight, General health, sex and diet of the patient, and based on the time and route of administration, rate of excretion of drugs from argasi connection according to the invention, can be used in the following way.

If this drug is used in the form of ointments, the amount of the compounds of the present invention contained in this ointment is from 0.01 to 10 wt.%.

In this preparation as ointment bases may be used an oil base (a natural wax, such as white beeswax or Carnauba wax; petroleum wax such as paraffin wax or microcrystalline wax; petroleum waxes such as liquid paraffin, vaseline oil, yellow petrolatum, plasticizer, Zelen 50W, silicone, vegetable oil, lard, beef tallow, simple ointment or plaster containing lead oleate); ointment base emulsion (emulsion of the type oil-in-water", this, as hydrophilic ointment or fast absorbing cream or emulsion of the type water-in-oil", such as hydrophilic petrolatum, purified lanolin, aquapol, Malin, Nevzlin absorbed ointment, hydrated lanolin, cold cream, hydrophilic plasticizing base); water-soluble base (macroglia ointment or saliva base); suspension ointment base (Ligeia basis, i.e., hydrogel base, such as an oil-free ointment, gel or lotion); or FAPG base (slicone); moreover, these ointment bases can be used both separately and in combination of two or more of these bases.

In addition, in the case of using ointment compound of the present invention is dissolved in solubilisers and accelerating the absorption of the agent and add to the above ointment basis.

The aforementioned term "solubilizers and accelerating the absorption agent" means the agent, in which the connection according to the invention is dissolved in a concentration of at least not less than 0.01 wt.% and which promotes absorption through the skin of the connections made in the form of ointment. This agent is lower alcander (for example, ethylene glycol, propylene glycol or butyleneglycol), alkalescent (for example, propylene carbonate or ethylene carbonate resulting), ether alkalicarbonate acid (for example, dimethyladipate, diethylacetal, isopropylacetate, diethylfumarate, diethylsilane or dipropylamino), ether highest alanovoy acid and glycerin (for example, monolaurin, dilauryl or Triowin), ether higher alkinoos acid and glycerin (for example, monaleen, diolein or triolein), alkilany ether highest alanovoy acid (for example, isopropylmyristate or atelierista), h is openft-2-one). These solubilizing and accelerating the absorption of agents can be used alone or as a mixture of at least two of these agents and can be added in a quantity sufficient to dissolve the compounds of the present invention. This amount is in the range of 2 to 200 wt. including 1 wt. H. compounds of the present invention. The upper limit of the specified interval, the number of agent is installed so that the agent does not adversely impact on the physico-chemical properties of the ointment.

Ointment containing the compound of the present invention may include, in addition to ointment bases, and other additives such as an emulsifier (for example, utverjdenie a polyoxyethylene castor oil, glycerol monostearate, servicesecurity or lauromacrogol), suspendisse agent (for example, polyoxyethyleneglycol, polyvinylpyrrolidone or sodium carboxymethylcellulose); an antioxidant (e.g., phenol or quinone); preservative (e.g., ether, peroxybenzoyl acid); water-retaining substance (for example, glycerin, D-sorbitol or propylene glycol); flavouring; dye; antiseptic; higher Allenova acid (e.g. oleic acid); and other drug medium is masiania solution, containing compound according to the invention, with the ointment base in accordance with the standard method. In the preparation of ointments to the ointment base can be added one or more adjuvants or additives. In addition, the ointment can be made by dissolving the compounds of the present invention in solubilisers and accelerating the absorption of the agent, and then mixing the resulting solution with ointment base and stirring the mixture under heating, with subsequent cooling and obtain the final mixture.

Ointment containing the compound of the present invention, can be used by the application to the affected skin areas from one to several times (for example, from 1 to 4 times per day.

Pasta or liniment (liquid ointment) containing the compound of the present invention can be prepared using the same basis and the same method as the ointment described above.

The term "lotion containing the compound of the present invention" means a fine and homogeneous suspension or partial solution of the active compound in a liquid medium, which can be added emulsifier.

If the connection according isob">

Liquid medium, which can be used in the lotion is water, a lower alcohol, a glycol, glycerol or mixtures thereof. As for spirits, for these purposes can be used all lower alcohols, which do not degrade the active ingredient and does not irritate the skin, such as methanol, ethanol, isopropyl alcohol, propanol or butanol. As the glycol can be used ethylene glycol, propylene glycol, butyleneglycol and lower monetary. Of these liquid media most preferred are water, lower alcohol or a mixture, since these environments increase the absorption of the active ingredient into the skin. The amount of used liquid media is preferably in the range from 5 to 1000 wt. including 1 wt. H. compounds of the present invention.

The lotion containing the compound according to the invention, can be added solubilizers and accelerating the absorption agent, in which the compound of the present invention is dissolved in a concentration of at least not less than 0.01 wt.% and which promotes absorption through the skin of the compounds of the present invention used as lotion; moreover, this agent is an ether alkalicarbonate acid (e.g. alkilany ether highest alanovoy acid (for example, isopropylmyristate or atelierista). These solubilizing and accelerating the absorption of agents can be used alone or as a mixture of at least two agents. The number of these agents is generally in the range from 5 to 5000 wt. including 1 wt. H. compounds of the present invention. The preferred content solubilizers and accelerating the absorption agent is in the range of 1-30 wt.%.

The emulsifier used in the lotion containing the compound of the present invention, is used for fine and homogeneous suspension of insoluble drugs in aqueous solution and must be nontoxic to the human body; this can be used pharmaceutically acceptable natural or synthetic emulsifier.

As natural emulsifiers can be used in a variety of emulsifiers of animal and vegetable origin, such as egg lecithin, soy lecithin or hydrogenated products, phosphatidylcholine, sphingomyelin, Arabian gum or gelatin. As a synthetic emulsifier can be used cationogenic, anionic or nonionic surfactants, this is a polyoxyethylene castor oil), such as HCO-60, HCO-50 or HCO-40. In addition, can be used polyoxyethylenesorbitan aliphatic acid, such as Polysorbate 80; an ester of glycerol and aliphatic acids, such as monocaprylin glycerol; polyoxyethylene aliphatic acid, such as monostearate polyoxyethylene 40; mono- (or di-glycerides of aliphatic acids with medium chain length (for example, mono- (or di-) glycerides C6-C12-aliphatic acid, such as diglycerin Caprylic acid monoglyceride Caprylic acid or diglyceride Caproic acid) or polyoxyethylene the glycerides, such as polyoxyethylene the glycerides of oleic acid.

The above emulsifiers can be used as a primary emulsifier and, if necessary, in combination with an auxiliary emulsifier. Auxiliary emulsifier, which is a standard and non-toxic to human body, can serve as cholesterol, agar, magnesium hydroxide, methyl cellulose or pectin.

These primary and secondary emulsifiers can be each used singly or in combination of two or more emulsifiers, respectively.

The amount of emulsifier, sodero of the invention and other additives, contained in the lotion, and is preferably from 0.1 to 10 wt. including 1 wt. H. compounds of the present invention.

For increasing the viscosity of the lotion of the present invention may be added to the agent that increases the viscosity. This increases the viscosity agent is any standard agent, which is usually added to increase the viscosity of the liquid and which is nontoxic to the human body. An example of such an agent is carboxypolymethylene. The agent that increases the viscosity of use if you need to get the lotion with a high viscosity. The content of an agent that increases the viscosity can vary depending on the desired viscosity of the lotion and is preferably from 0.01 to 5 wt.%.

This lotion can optionally contain a stabilizer, and other additives commonly used for the manufacture of lotions, for example, a flavoring, a colorant, antiseptic or higher Allenova acid, such as oleic acid, or other medicines used for the treatment of skin diseases.

The lotion containing the compound of the present invention can be obtained in a standard way.

Lotion containing(e.g., from one to four times per day. If the lotion has a low viscosity, the composition of this lotion can be introduced into the vessel for spraying and applied on the skin by spraying.

In the case when the connection according to the invention is used in the form of eye drops or nose drops, the solvent is sterile distilled water, particularly distilled water for injection. The concentration of the active compounds in these preparations is in the range from 0.01 to 2.0 wt/vol.% and may be increased or decreased depending on the purpose of use.

Eye drops or nose drops containing compound according to the invention may optionally include various additives such as a buffer, an isotonic agent, solubilizers agent; a preservative; an agent that increases the viscosity; chelate forming agent; an agent that regulates pH; or aromatic substance.

As the buffer may be used, for example, phosphate buffer (e.g. phosphate sodium - centripetal or potassium phosphate - dailypost), borate buffer (for example, boric acid - borax), citrate buffer (for example, sodium citrate - sodium hydroxide), tartrate buffer (for example, tartaric acid - sodium tartrate), at or sodium carbonate - boric acid) or amino acid (e.g., monosodium glutamate or-aminocaproic acid).

Isotonic agent is saharel, in particular sorbitol, glucose or mannitol, polyhydric alcohol, in particular glycerol or propylene glycol, salt, such as chloride or borax or boric acid, etc.

Solubilization agent is a surfactant, such as polyoxyethylene sorbitan monooleate (Polysorbate 80), polyoxyethylenated, polyethylene glycol or utverjdenie a polyoxyethylene castor oil, etc.

Preservatives are, for example, Quaternary ammonium salt such as benzalkonium chloride, chloride benzene or chloride of cetylpyridinium; aired parahydroxybenzoic acid, such as methyl parahydroxybenzoate, metilparagidroksibenzoat, sodium propyl parahydroxybenzoate or butylperoxybenzoate; benzyl alcohol, finitely alcohol, sorbic acid or its salt; thimerosal, chlorbutol, dehydroacetic sodium, methylparaben or propylparaben.

An agent that increases the viscosity is, for example, polyvinylpyrrolidone, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, hypromellose or carboxyl is, etc.

Agent regulating the pH is hydrochloric acid, citric acid, phosphoric acid, acetic acid, tartaric acid, sodium hydroxide, potassium hydroxide, sodium carbonate or sodium bicarbonate, etc.

Aromatic substance is 1-menthol, borneol, camphor (for example, dl-camphor or eucalyptus oil, etc.

Eye drops containing compound according to the invention can have a pH from about 4.0 to about 8.5; and nose drops can also have a pH from about 4.0 to about 8.5.

The concentration of active ingredient in the eye drops may vary depending on the symptoms or the nature of inflammation, and is usually in the range from about 5.0 to about 1000 μg per intake. This drug can be introduced from one to several times (for example, from one to four times per day.

The term "aerosol containing compound according to the invention" means a pharmaceutical product, which may be applied by spraying the solution or suspension of the active compound using the liquefied gas or compressed gas under pressure which fills the same vessel or another vessel. The aerosol can be obtained by dissolving the compounds according to izopet the m solubilizers and accelerating the absorption agent, as described above, and then adding, if necessary, additives such as a pH Adjuster or antiseptic mentioned above, and the subsequent sealing of the container using the valve after the compression of the propellant. A suitable propellant is dimethyl ether, liquid natural gas, carbon dioxide, gaseous nitrogen, substituted gaseous Flon and other standard propellants.

The aerosol may also contain a refrigerant, such as 1-methanol, camphor, methyl salicylate, etc.

Inhalant or spray (spray solution) containing the compound according to the invention, can be obtained by the methods described above to obtain an aerosol. Inhaler or respirator can be used for inhalant, and a vessel for spraying can be used to spray.

If the connection according to the invention in the form of a suppository, the suppository can be obtained in a standard way using the framework, which is commonly used for the manufacture of suppositories. The number of compounds according to the invention contained in suppositories may vary depending on the age or symptoms of the patient, and is preferably from 0.1 to 60 lo and grease of animal and vegetable origin, in particular olive oil, corn oil, castor oil, oil of cotton seeds, oil from sprouted wheat, cocoa butter, beef tallow, lard, fat bristle, turtle oil, squalene or utverjdenie oil, mineral oil and mineral oil, such as petroleum jelly, white semi-solid paraffin, solid paraffin, liquid paraffin, digidrirovanny lanolin or silicone oil, waxes such as jojoba oil, Carnauba wax, yellow beeswax or lanolin, partially or fully synthetic ester of glycerol and aliphatic acids, such as mono-, di - or triglyceride of medium or higher aliphatic acid, such as saturated aliphatic acid with a straight chain (e.g., lauric acid, myristic acid, palmitic acid, or stearic acid) or unsaturated aliphatic acid with a straight chain (e.g., oleic acid, linoleic acid or linolenic acid). Examples of commercially available products are Witepsol [produced Dynamitnobel Co., a mixture of mono-, di - and triglycerides of saturated C12-C18saturated aliphatic acids, and more specifically, Witepsol H-series (for example, Witepsol H5, H12, H19, H32, H35, H37, H39, H42, H175 or H185). Witepsol series is example, Witepsol S52, S55 or S58); Pharmasol (manufactured by Nippon Oils and Fats Co.); Izokukai (produced by Kao Co.); the drug SB (manufactured Kanegafuchi Chemical Co. and Taiyo Yusi Co.; a mixture of mono-, di - and triglycerides of saturated C12-C18-aliphatic acids, and more specifically, SB-H, SB-E or SB-AM); Napata (produced Henkel AG); Sapoyer (made Gattfords Co.; a mixture of mono-, di - and triglycerides of saturated C10-C18-aliphatic acid, and, in particular, Sapoyer NA, Sapoyer OS, Sapoyer AS Sapoyer BS, Sapoyer BM or Sapoyer DM); Methasterone (made Dynamitnobel Co.; a mixture of mono-, di - and triglycerides of saturated C10-C18-aliphatic acid, and, in particular, Methasterone A, AB, B, BB, BC, BCF, C, D, E or BD, and Methasterone 299); or Miglyol 810 or Miglyol 812 (manufactured Dynamitnobel Co.; a mixture of triglycerides of saturated C8-C12-aliphatic acids, in particular one or more of them may be, but not necessarily introduced with the introduction of the above-mentioned partially or fully synthetic ester of glycerol and aliphatic acid). Additionally, there may be mentioned and other synthetic products, such as polyethylene glycol or polyoxyethylene alcohol. These bases are used in amounts of from 25 to 99.9% by the full weight of the suppository.

Suppository containing compound of the present invention, may be made in the form of various dosage forms, such as a rectal suppository, which is solid at ordinary temperature and melts at body temperature; ointment or liquid enema, which can be obtained by dissolution or suspension of the compounds of the present invention in the liquid base; soft capsule for rectal insertion, or injection for rectal administration.

The outer product for local use in accordance with the present invention can be used for the prevention or treatment of various diseases, for which there are already indications for oral introduction of the compounds of the present invention, for example for immunosuppression in organ transplantation or bone marrow for the treatment of various autoimmune or allergic diseases. In particular, since this compound has pharmacological activity, in particular immunosuppressive, or antimicrobial, this connection can be used for the prevention or the x of organs or tissues (such as the heart, kidneys, liver, lungs, bone marrow, cornea, pancreas, small intestine, limb, muscle, nerve, bone marrow, duodenum, skin or cells of pancreatic islet, etc., including xenografts), homologous disease type reactions "graft versus host" had a bone marrow transplant (GvHD), autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, nephrotic lupus, Hashimoto's thyroiditis, multiple sclerosis, severe psevdomatematicheskoe myasthenia gravis, diabetes type I, diabetes mellitus adult type II, uveitis, nephrotic syndrome, steroid-dependent and steroid-resistant nephrosis, pustular atrophicans, allergic encephalomyelitis, glomerulonephritis, etc.,; and infectious diseases caused by pathogenic microorganisms.

The active compound can also be used for the treatment of inflammatory, proliferative and hyperproliferative skin diseases and cutaneous manifestations of immunologically mediated diseases, such as psoriasis, psoriatic arthritis, diffuse neurodermitis (atopic dermatitis), contact dermatitis, and other eczematous dermatitises, seborrhoeic eczema, red plaskolite, erythema, skin eosinophilia, acne, alopecia areata, eosinophilic fasciitis, and atherosclerosis.

More specifically, the connection according to the invention can be used for hair restoration, for example for the treatment of baldness in male and female type, or senile alopecia by preventing hair loss and/or stimulate germination, formation and growth of hair.

In addition, the connection according to the invention can be used for the treatment of respiratory diseases such as sarcoidosis, pneumosclerosis, idiopathic interstitial pneumonia, and reversible obstruction of the Airways, including such conditions as asthma, such as bronchial asthma; asthma in children; allergic asthma; hereditary asthma; acquired bronchial asthma; asthma caused by powdered allergens, in particular chronic and chronic intractable asthma (e.g. late-diagnosed asthma and hypersensitivity of the respiratory tract, bronchitis, etc.

The compound of the present invention can also be used for treatment of liver damage associated with ischemia.

In addition, soedineniya; keratoconjunctivitis; keratitis; vernal conjunctivitis; uveitis associated with Behcet's disease, herpetic keratitis; conical cornea; epithelial corneal dystrophy; corneal opacity white; disease of the eye; corroding ulcer of the cornea Morena; scleritis; severe ophthalmopathy, severe intraocular inflammation; etc.

The connection according to the invention can also be used to prevent or treat inflammation of the mucous membranes or blood vessels (such as leukotriene B4-mediated diseases; stomach ulcer; vascular damage associated with ischemia and thrombosis, ischemic bowel disease, inflammatory bowel disease (such as Crohn's disease, ulcerative colitis and necrotizing enterocolitis) or damage of the small intestine associated with thermal burns.

In addition, the connection according to the invention can be used for treating or preventing renal diseases such as interstitial nephritis syndrome?, hemolytic-uremic syndrome and diabetic nephropathy; nervous diseases selected from the group including dermatomyositis, Guillain-Barre syndrome, Meniere's disease and radiculopathy; anaplasia, aplastic anemia, gipoplasticheskaya anemia, idiopathic thrombocytopenic purple, autoimmune hemolytic anemia, agranulocytosis and americaplay; bone diseases, including osteoarthritis; respiratory diseases, including sarcoidosis, pneumosclerosis and idiopathic interstitial pneumonia; skin diseases, including dermatomyositis, vitiligo, ichthyosis, sensitivity to light exposure, and T-cell lymphoma of the skin; circulatory diseases, including atherosclerosis, inflammation of the aorta (aortic), polyarteritis polyarteritis and micardis; collagenoses, including scleroderma, granulomas's granulomatosis, Sjogren syndrome; eosinophilias of fasciitis; periodontal disease; nephrotic syndrome; haemolytic uraemic syndrome; and degeneration of the muscles.

In addition, the connection according to the invention has the indications for treatment of diseases such as inflammation of the small intestine or allergies, such as diseases caused by intestinal bacteria, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, or ulcerative colitis; as well as food allergies, the symptoms of which are identified at sites remote from the gastrointestinal tract, for example migraine, rhinitis and eczema.

The connection according to the invention also has indications for its use as an antimicrobial agent, and therefore it can be used to treat diseases caused by pathogenic microorganisms, etc.

In addition, the connection according to the invention can be used for the prevention or treatment of malignant rheumatoid arthritis, amyloidosis, fulminant hepatitis, syndrome Shay-Drager, pustular psoriasis, diseases behceta, systemic lupus erythematosus, endocrine ophthalmopathy, progressive systemic sclerosis, mixed collagenosis, syndrome of inflammation of the aorta, Wegener granulomatosis, chronic active, hepati the immune inflammation of the adrenal gland) autoimmune), autoimmune oophoritis, cold haemagglutination, proximale cold hemoglobinuria, pernicious anemia, T-cell leukemia adults, autoimmune atrophic gastritis, lupus hepatitis, canalave-interstitial nephritis, membranous nephritis, amyotrophic lateral sclerosis, rheumatic fever, post-infarction syndrome and sympathetic oftalmica.

The connection according to the invention can also be used in combination with other immunosuppressants, steroids (prednisolone, methylprednisolone, dexamethasone, hydrocortisone, etc.,) or nonsteroidal anti-inflammatory drugs. Of these other immunosuppressants especially preferred are azathioprine, brevemente, desoxypeganine, mizoribine, 2-morpholinobutyrophenone, cyclosporin, rapamycin, tacrolimus monohydrate.

The invention is illustrated by the following pharmaceutical examples.

Pharmaceutical drug 1

Hydrochloride of 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol (hereinafter referred to as Compound (1) (1 g) was dissolved in 19 g of hydrophilic vaseline, heating at 60oC, and then cooled while stirring, in Manie (1) (1 g) was thoroughly mixed with 19 g of plasticizer (gelatinizing hydrocarbon) in a mortar for about 30 minutes, as a result, we received an ointment containing 5% of Compound (1).

Pharmaceutical drug 3

Molten Witepsol H15 (72,47 g) at 40oC was added the Compound (1) (30 mg) and the resulting mixture is stirred for a suspension of the Compound (1). Container, calculated on the weight of 725 mg, each filled the obtained homogeneous mixture, and received a suppository containing 0.3 mg of the Compound (1) per lot 725 mg.

Pharmaceutical drug 4

To 70 ml of sterile distilled water was added 0.2 g of polyvinyl alcohol, which is then dissolved with stirring and heating at 70oC. To the resulting solution was added a homogeneous suspended castor oil, utverjdenie a polyoxyethylene 60 (0.1 g), after which the mixture was cooled to room temperature. Then to the solution was added 0.2 g of Compound (1), 0.5 g of dinatriumfosfaatti, 0.1 g of sodium phosphate, 0.8 g of sodium chloride and 0.007 g of chloride benzathine. To the resulting solution was added to sterile distilled water and was given eye drops containing Compound (1) in full 100 ml.

Pharmaceutical drug 5

To 70 ml of sterile distilled water was added 0.4 g of Compound (1), 0.2 g of sodium citrate, 0.1 g of the profiled water, as a result, were given nasal drops containing Compound (1) in full 100 ml.

Pharmaceutical drug 6

To 100 mg of the Compound (1) was added 1 ml of isopropylmyristate and 4 ml of ethanol at room temperature and got the lotion containing 2% of Compound (1).

Industrial application

External preparation containing the compound according to the invention, can be used by local applications to inhibition reactions of rejection of the transplanted organ or bone marrow or for the treatment of autoimmune or allergic diseases.

The effect of topical application of 2-amino-2-(2-(4-octylphenyl)ethyl)propane-1,3-diol (FTY 720) for allergic reaction delayed-type mice caused methylated human serum albumin.

Method

Allergic reaction of the delayed type (DTH) induced in accordance with a modified method Uyeki et al. Methylated human serum albumin (MeHSA) received in accordance with the method of Crowle et al. Female BALB/C mice were senzibilizirani by dorsal subcutaneous injection of 100 μl of 0.25% MeHSA. Four days sensitized mice were administered by subcutaneous injection of 25 μl of 0.25% is of cosmometry (Unicom, TK-101). The amount of swelling was calculated by finding the difference between the volumes of the rear foot to the introduction of the antigen and 24 h after injection, and the result was considered as an indicator of DTH. The drug was dissolved in ethanol and applied (50 μl/site) on the right rear foot consistently within 5 days from the day of sensitization. The last application was carried out for 1 h before injection of the antigen.

Results

FTY 720 showed dose-dependent inhibition of DTH induced MeHSA, when applying 0.01~ 1%-aqueous solution on the right hind leg, this inhibitory effect was statistically significant at all tested concentrations (see table).

1. The local drug application for immunosuppression and treatment of autoimmune or allergic diseases on the basis of activitiesthese substances and specific additives, characterized in that as activitiesthese substance contains 2-amino-2-(2-(4-octylphenyl)ethyl propane-1,3-diol or its pharmaceutically acceptable acid additive salt in an effective amount.

2. The drug under item 1, characterized in that it is a dosage form selected from the group including ointment, paste, liniment, lotion, band-AIDS, the creation, applied with a brush, nose drops, cream, plaster and tampon.

3. The drug under item 1, characterized in that it is an ointment containing 0.01 to 10 wt.% activitiesthese connection.

4. The drug under item 1, characterized in that it is a lotion containing 0.01 to 10 wt.% activitiesthese connection.

5. The drug PCP.3 and 4, characterized in that it further comprises solubilizers and accelerating the absorption of the agent.

6. The drug under item 1, characterized in that it is a eye drops or nose drops containing 0.01 to 2.0 wt./vol.% activitiesthese connection.

7. The drug under item 1, characterized in that it is an aerosol, inhalant or spray.

8. The drug under item 1, characterized in that it is a suppository, containing 0.1 - 60 mg activitiesthese connections per dose.

 

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