Improved methods and compositions for safe and effective treatment of telangiectasia

FIELD: medicine.

SUBSTANCE: present group of inventions refers to medicine, namely to dermatology, and concerns treating telangiectasia or related symptoms. To this effect, an involved skin area is coated with a composition containing from approximately 0.4 wt % to approximately 0.6 wt % brimonidine providing its blood serum or plasma concentration, Cmax of approximately 54±28 pg/ml or less and AUC0-24h of approximately 568±277 pg·h/ml or less.

EFFECT: method provides the effective treatment of telangiectasia or related symptoms with no side local and systemic effects.

20 cl, 6 dwg, 6 tbl, 3 ex

 

CROSS-REFERENCE TO RELATED APPLICATIONS

In accordance with § 119(e) of section 35 of the Code of Federal laws of the United States, this application is entitled to priority of provisional patent application U.S. No. 61/282753 filed March 26, 2010, the contents of which are fully incorporated into the present description by reference.

The prior art INVENTIONS

Telangiectasias are extremely common skin diseases. Telangiectasias are visible small red, purple or blue surface blood vessels, which can be located on the face, upper chest, neck, or other parts of the body. Telangiectatica blood vessels, which may include swollen blood vessels, spider veins, red skin spots, purple skin spots or blue skin spots, atypical and do not carry any of the vital functions in the body.

Telangiectatica blood vessels may appear independently, as well as result from or occur simultaneously with disease of the skin or internal disease. Telangiectasias can develop anywhere on the body, but most considerably they appear on the skin. Telangiectasias include telangiectasias unclear etiology or primary telangiectasias, which include stretching blood is red vessels of unknown etiology. Generalized telangiectasia unclear etiology (GET) are characterized by the distribution reticulation throughout the body. Other primary telangiectasias include serpiginosa the angioma, ataxia-telangiectasia, varicose small veins, such as zvezdoobrazovanie veins, angiomas and spider nevi. Some other examples of conditions, syndromes, diseases and disorders that may include telangiectasias, are the CREST syndrome (an acronym of calcification (Calcinosis, Raynaud's phenomenon (Raynaud's phenomenon), dysfunction of the esophagus (Esophageal dysfunction), sclerodactyly (Sclerodactyly, and telangiectasia (Telangiextasis)), hereditary hemorrhagic telangiectasia (disease Osler-Weber-Rendu), ataxia-telangiectasia, rosacea (also known as acne rosacea), basal cell carcinoma, scleroderma, teleangiectasias nevus, unilateral nevidna telangiectasia congenital telangiectatica marble skin, hereditary hemorrhagic telangiectasia. Secondary telangiectasia may arise from photochemical damage (such as when eritrodermii interfollicular tissue in the neck), radiation therapy, and steroid therapy, including prolonged exposure to corticosteroids. Chronic liver disease and collagen vascular diseases can also izvati the telangiectasia.

Telangiectasia may be a symptom of rosacea. However, rosacea also includes erythema and, thus, is a syndrome different from telangiectasias.

Currently used methods of treatment that improves the appearance of telangiectasia include laser therapy, phototherapy, including IVS IPLs, electrocoagulation and electro-optical synergy (ELOS), which combines intense pulsed light energy and bipolar radio frequency (RF) energy in a single pulse (Sadick NS, et al., J. Drugs Dermatolog. 4: 181-186, 2005).

Brimonidine, a selective α2-adrenergic agonist, used either as monotherapy or in related therapy to lower intraocular pressure (IOP) in the treatment of glaucoma and ocular hypertension (GG) from the moment of its approval for treatment in 1996. The most common side effects associated with the intake of brimonidine are dry mouth, fatigue/drowsiness, headache, mild hyperemia, blurred vision and foreign body sensation. Hypertension, palpitations and fainting were reported in less than 3% of patients in clinical studies, including ophthalmic application of brimonidine. Cm. McGhie, Journal of the Pharmacy Society of Wisconsin, May/June 2001, on the world wide web: pswi.org/professional/pharmaco/brimonidine.pdf and applied with Alki. The results of the study to determine the optimal dose in patients with glaucoma or ocular hypertension showed that, despite a higher effective dose of 0.5% (m/m) at an early stage of treatment, the dose of 0.5% (m/m) and 0.2% (m/m) was equally effective after two weeks of treatment and the dose of 0.5% (m/m) caused the onset of systemic and ocular side effects to a greater extent than the dose of 0.2% (m/m). See, for example, Walters, Survey of Ophthalmology, 1996, 41: S19-S26. Ophthalmological preparations containing 0.2% (m/m) of brimonidine, was used for long-term treatment of glaucoma and ocular hypertension, while preparations containing 0.5% (m/m) of brimonidine was used only for short-term treatment in order to prevent spikes postoperative intraocular pressure. In order to reduce various ocular and systemic side effects associated with the ophthalmic application of 0.2% (m/m) of brimonidine, ophthalmic preparations containing low concentrations of brimonidine, for example of 0.15% (m/m) or 0.1% (m/m), were subsequently developed and used for long-term ophthalmologic applications.

There were reports that brimonidine effective in the treatment of telangiectasias. See, for example, US patent 7838563 (DeJovin et al.). It was also reported that brimonidine was effective in the treatment of erythema caused by rosacea. See, nab is emer, US 10/853585 (DeJovin et al.). To ensure safety and to avoid any unwanted side effects in a previous clinical study used by 0.2% (m/m) of brimonidine tartrate as a "larger" doses for the treatment of erythema. Cm. US 2009/0061020 (Theobald et al.).

In the present invention it was unexpectedly found that the topical introduction of brimonidine on the affected area of the skin has a much less systemic effects than topical ocular application of brimonidine. It was found that although systemic exposure increases with the applied dose of brimonidine, statistical analysis showed that the increase in systemic exposure (Cmaxwas not proportional to the dose of, for example, an increase in the value of Cmaxit was much smaller than the increase in dose. In addition, it was found that, in contrast to topical ocular application of brimonidine, topical application of higher than 0.2% (m/m) of brimonidine on the area of skin affected by telangiectasia or related symptoms, has led to increased efficiency without appreciable loss of efficiency over time. When testing the effects of higher concentrations of brimonidine unacceptable adverse effects associated with taking drugs, was not observed.

Thus, a higher concentration of brimonidine, for example from about 3% (m/m) to 10% (m/m), can now be used in more sophisticated methods and compositions for safe and effective treatment of telangiectasias or associated symptoms.

The INVENTION

In one General aspect, embodiments of the present invention relate to a method of implementing a safe and effective treatment of telangiectasias or symptoms related to the patient. The method comprises topical application to the skin area affected by telangiectasia or symptoms, topical compositions containing from about 0.3% to about 10% by weight of brimonidine and a pharmaceutically acceptable carrier, where the topical introduction leads to indicators of brimonidine in serum or plasma with a mean value of Cmaxabout 54±28 PG/ml or less and a mean AUC0-24habout 568±277 PG·h/ml or less.

In another General aspect, embodiments of the present invention relate to a method for producing a packaged product to ensure safe and effective treatment of telangiectasias or related symptoms in a patient, including:

(1) preparation of topical compositions containing from about 0.3% to about 10% by weight of brimonidine and a pharmaceutically acceptable carrier;

(2) the development of guidelines for topical introduction to topical compositions for the region is to be the skin, affected by telangiectasia or symptoms, for safe and effective treatment and

(3) provide a topical composition and instructions in a single package, in which topical introduction leads to indicators of brimonidine in serum or plasma with a mean value of Cmaxabout 54±28 PG/ml or less and a mean AUC0-24habout 568±277 PG·h/ml or less.

In a preferred variant of the invention, the topical composition is used or covered versions of the implementation of the present invention contains from about 0.4% (m/m) to about 0.6% (m/m) of brimonidine tartrate.

In another preferred embodiment of the invention telangiectasia telangiectasia is caused by rosacea.

Other aspects, features and advantages of the invention will be apparent from the following description, including a detailed description of the invention and its preferred embodiments and the accompanying claims.

BRIEF DESCRIPTION of DRAWINGS

The above summary and the following detailed description of the invention will be better understood when viewed in conjunction with the attached images. With the purpose of illustrating the invention, in the image shown embodiments of the invention, which are preferred onpresent moment. However, it should be understood that the invention is not limited to images.

On the images:

Fig.1 - a snapshot of the patient's face, made in accordance with RBX Red™ pre-processing of the initial state, the evaluation of redness entire face was 126,29;

Fig.2 - a snapshot of the patient's face with Fig.1, made in accordance with RBX Red™ 30 minutes after pre-treatment with 0.5% (m/m) of brimonidine tartrate, evaluation of redness entire face 88,15, 30.20mm% decreased compared to the initial state;

Fig.3 - a snapshot of the patient's face with Fig.1, made in accordance with RBX Red™ 3 hours after pre-treatment with 0.5% (m/m) brimonidina the tartrate, evaluation of redness entire face 78,03, 38,22% decreased compared to the initial state;

Fig.4 is a snapshot of the patient's face with Fig.1, made in accordance with RBX Red™ 6 hours after pre-treatment with 0.5% (m/m) brimonidina the tartrate, evaluation of redness entire face 84,90, 32,77% decreased compared to the initial state;

Fig.5 - snapshot of the patient's face with Fig.1, made in accordance with RBX Red™ 9 hours after pre-treatment with 0.5% (m/m) brimonidina the tartrate, evaluation of redness entire face 97,93, 22,46% decreased compared to the baseline condition; and

Fig.6 is a snapshot of the patient's face with Fig.1, made in accordance with RBX Red™ 12 hours after pre-treatment is 0,5% (m/m) brimonidina the tartrate, evaluation of redness entire face 104,15, 17,53% decreased compared to the initial state.

DETAILED description of the INVENTION

Various publications, articles and patents cited or described in the prior art and in the description; each of these references are fully incorporated in the present description by reference. The documents under discussion, actions, materials, devices, articles, etc. that were included in the present description, are intended to provide conditions for the implementation of the present invention. Such a discussion is not an admission that any or all of these materials form part of the prior art in respect of any of the disclosed or claimed invention.

If not stated otherwise, all technical and scientific terms used in this description, have the same meaning, what is usually understood by any person skilled in the art to which this invention relates. In other cases, some used herein, the terms have the meanings as indicated in the description. All patents, published patent applications and publications cited in this description are incorporated by reference as if they were set forth fully herein. It should be noted that here and in the accompanying claims, the singular number include the plural, unless the context clearly dictates and the second.

In the framework of the invention "telangiectasia or associated symptoms" refers to a visible persistent permanent abnormal dilation of blood vessels, such as arterioles and venules. Visible blood vessel is a blood vessel in a line that is visually perceptible to an observer without the aid of magnifying equipment (except points, usually used by the observer). Telangiectasias can be associated with numerous conditions, syndromes, diseases and disorders. For example, telangiectasia of the face may be associated with age, sun and alcohol. Other diseases, disorders, conditions and syndromes associated with telangiectasia, include, without limitation, for example, the following: scleroderma, hereditary haemorrhagic telangiectasia (disease Randy-Osler-Weber), ataxia-telangiectasia, spider hemangioma, congenital teleangiectasias marble skin syndrome bloom syndrome Klippel-Crinone-Weber disease, Stergia-Weber, pigmentary xeroderma, flaming nevus, generalized telangiectasia unclear etiology (GET), serpiginosa the angioma, ataxia-telangiectasia, spider nevus, CREST syndrome, hereditary haemorrhagic telangiectasia (disease Randy-Beber-Osler), ataxia-telangiectasia, basal cell is epithelioma, scleroderma, unilateral avoidnow the telangiectasia and congenital teleangiectasias marble skin.

In one specific embodiment of the present invention, the term "telangiectasia or associated symptoms include telangiectasia associated with or formed as a result of rosacea, i.e., telangiectasia or associated symptoms in patients with rosacea.

In another specific embodiment of the present invention, the term "telangiectasia or associated symptoms include telangiectasia caused by the sun/light damage.

The term "telangiectasia or associated symptoms include varying degrees or classes telangiectasias or related symptoms, from mild to severe. Such degrees or classes can be measured by means known in the field of methods such as the measurement of the total assessment telangiectasia (TGA).

In the light of the present invention, the affected telangiectasia skin area or are prone to defeat telangiectasia may be determined using any of the diagnostic signs or means known in this field, and it can be treated by the methods in accordance with the variants of implementation of the present invention.

The effectiveness of treatment can be estimated using a method known in this field. N the example, efficiency can be assessed by determining the extent of the improvements according to the assessment by the TGA and duration of improvement.

Used herein, the term "brimonidine" refers to the compound (5-bromo-cinoxacin-6-yl)-(4,5-dihydro-1H-imidazol-2-yl)-amine having the structural formula (I):

Formula (I),

and any pharmaceutically acceptable salt of this compound, including, but not limited to, brimonidine tartrate.

Used in the present description, the phrase "pharmaceutically acceptable(s) salt(s)" means those salts of compounds correspond to the safety and efficacy for topical administration to mammals, and that they possess the desired biological activity. Pharmaceutically acceptable salts include salts of acidic or basic groups present in these compounds. Pharmaceutically acceptable salt accession acids include, but are not limited to, the following salts include hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, Pantothenate, bitartrate, ascorbate, succinate, maleate, getitemat, fumarate, gluconate, glucuronate, saharat, formate, benzoate, glutamate, methanesulfonate, aconsultant, bansilalpet, p-toluensulfonate, pamoate (for example, 1,1'-methylene-bis-(2-hydroc and-3-aftout)). Some used in the present invention compounds can form pharmaceutically acceptable salts with various amino acids. Suitable basic salts include, but are not limited to, salts of aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine. For an overview of pharmaceutically acceptable salts see BERGE ET AL., 66 J. PHARM. SCI. 1-19 (1977), incorporated by reference.

Used in the present description, the term "composition for topical introduction", "topical composition" or "topical composition" means any composition or a composition that is pharmaceutically and/or cosmetically acceptable topical delivery of these compounds in accordance with a variant embodiment of the invention. Exemplary forms of the drug, which can be used for topical application in the variants of implementation of the present invention include, but are not limited to, sprays, aerosols, solutions, lotions, gels, creams, ointments, pastes, ointments, emulsions and suspensions.

Used in the present description, the term "composition for topical introduction" also includes input locally and acting locally compositions, such as compositions used with implants, injections or patches.

The choice of compositions for topical introduction will depend on several factors, including the x, but not limited to: the nature of the symptoms for the treatment or prevention, physico-chemical characteristics of a particular input connection and the other present fillers, their stability in the mixture, the aesthetics of any proposed structure, the availability of production equipment and the limitation on costs.

Used in the present description, the term "composition" is intended to cover products that contain certain components in the specified quantity, and also includes any product that results, directly or indirectly, from combination of the specified ingredients in the specified amounts.

Used in the present description, the term "patient" means any animal, preferably a mammal, most preferably a human, which is injected or introduced connection or topical formulations in accordance with a variant embodiment of the invention. Preferably, the patient needs or was the object of observation or experiment, treatment, or prevention of telangiectasias or associated symptoms.

Used in the present description, the term "instructions", when used in the context of the Packed product, includes publications, records, charts, or any other means of expression that can be used for communication practical value Packed the CSOs of the product for his intended purpose. The instructions can, for example, be attached to or included in the container of the packaged product.

Used in the present description, the term "treatment" or "treat" refers to the improvement, prevention or change telangiectasias or related symptoms, for example, by reducing or delaying the start of the visibility of small, red, purple or blue superficial blood vessels on the surface of the skin damaged by telangiectasia or symptoms.

Used in the present description the expression "safe and effective amount of brimonidine" means the number of brimonidine, which is effective for the treatment of telangiectasias or related symptoms without causing unacceptable effects associated with taking drugs when administered to a patient.

Used in the present description, the term "unacceptable side effects associated with the drug," and "unacceptable adverse drug reaction" shall mean damage or undesirable results, reaching such a degree of severity that the regulator deems the product unacceptable for its intended use.

In the present invention it was found that topical application of a safe and effective amount of brimonidine, for example, a topical composition comprising about is about 0.3% to about 10% by weight of brimonidine, on the area of skin affected by telangiectasia or related symptoms, provides effective treatment of telangiectasias or related symptoms without causing unacceptable adverse drug reactions. For example, it was found that topical application of the topical composition, including increased concentration of brimonidine, on the area of skin affected by erythema or related symptoms, has led to a distinct dependent on the dosage increase efficiency and increase exposure. However, statistical analysis showed that the increase in systemic exposure (Cmaxwas not proportional to the dose, such as increasing the value of Cmaxit was much smaller than the increase in dose. When exposed to higher concentrations of brimonidine unacceptable side effects were observed. Topical skin exposure to all concentrations and modes resulted in a significant reduction of systemic exposure of brimonidine in comparison with the effects of eye drops used in accordance with the recommendations on the label ophthalmic products.

Such excellent clinical indicators of higher concentrations of brimonidine, for example from about 0.3% to about 10% by weight, were not previously reported. This opening is amazing and Noida the tion, especially in light of the previously described indicators of the effectiveness and safety of brimonidine in the ophthalmic application, where a significant loss of efficacy over time was observed with 0.5% (m/m) composition of brimonidine, and preferably prolonged use of much lower concentrations of brimonidine, such as 0.1% or 0.15% by weight, as lower concentrations provide improved portability, while maintaining the effectiveness of lowering IOP.

Thus, in one General aspect, embodiments of the present invention relate to method safe and effective treatment of telangiectasias or related symptoms in a patient, comprising the topical application on the skin area affected by telangiectasia or symptoms, topical compositions containing from about 0.3% to about 10% by weight of brimonidine and a pharmaceutically acceptable carrier, where topical application leads to indicators of brimonidine in serum or plasma with a mean value of Cmaxabout 54±28 PG/ml or less and a mean AUC0-24habout 568±277 PG·h/ml or less. The average value of Cmaxand the average AUC0-24hcorrespond to the indicators of brimonidine in serum or plasma after eye treatment eye drops 0.2% (m/m) PSOM Brima is Idina tartrate, in accordance with the recommendations on the label ophthalmic products.

In one of the embodiments of the invention, the composition for topical application contains about 0,3%, 0,5%, 1,0%, 1,5%, 2,0%, 2,5%, 3,0%, 3,5%, 4,0%, 4,5%, 5,0%, 5,5%, 6,0%, 6,5%, 7,0%, 7,5%, 8,0%, 8,5%, 9,0%, 9,5% or 10.0% by weight of brimonidine, in particular of brimonidine tartrate.

In another embodiment of the present invention, the composition for topical application contains about 0.4%, slightly less than 0.45%, about 0.5%, about 0.55%, respectively, or approximately 0.6% by weight of brimonidine, in particular of brimonidine tartrate.

In a preferred embodiment, the topical composition contains about 0.5% by weight of brimonidine, in particular about 0.5% by weight of brimonidine tartrate.

For the treatment or prevention of telangiectasias or related symptoms, in light of the disclosure of the present invention, the composition for topical application according to the invention can be tapicerki applied directly on the affected area of the skin by any conventional method known in the art, for example using a dropper, applicator or cotton swab, as a fine spray through a spray applicator, using intradermal or transdermal patches or simple application of the composition according to the invention to the affected area fell the judgments, sponge, pad or cloth. Generally, the amount of the topical composition according to the invention applied on the affected skin area in the range from about 0.0001 g/cm2the skin surface to about 0.05 g/cm2preferably 0.002 g/cm2to about 0.005 g/cm2the surface of the skin.

In various aspects of the application of the topical composition can significantly improve telangiectasia within about 2 minutes after application, within 5 minutes after application or within 10 minutes after application. In some aspects, the composition may be as effective after approximately 30 minutes after application, and the ameliorative effects can last up to about 2 hours to about 4 hours to about 8 hours to about 12 hours to about 18 hours to about 24 hours or longer. Accordingly, in some aspects, the composition can tapicerki be applied to the skin with symptoms of telangiectasia once a day, twice a day, three or more times a day.

The methods according to the present invention can be used in combination with one or more other modalities and/or treatment with the aim of providing more effective treatment of telangiectasias. In some aspects, the topical compositions can be used in combination with schemes the th treatment and processing of medication for the treatment of dermatological diseases, such as described in THE MERCK MANUAL 811-830 (Keryn A. G. Lane et al. eds. 17th ed. 2001), which is fully incorporated into the present application by reference.

In one aspect of the topical compositions can be used in combination with systemic antibiotics or retinoids, including, but not limited to, antibiotics, for oral administration, such as tetracycline, minocin, minocycline, erythromycin, doxycycline, and retinoids for ingestion, such as isotretinoin (such as Accutane or Roaccutance).

In other aspects described herein topical compositions can be used in combination with other topical therapies, including, but not limited to, topical composition comprising metronidazole, hydrogen peroxide, benzoyl peroxide, lipoic acid and azelaic acid, and sulfur drugs; antibiotics topical application, such as metronidazole, clindamycin, and erythromycin; anti-parasitic, such as permethrin and ivermectin; topical retinoids such as tretinoin, adapalene, tazarotene; or topical steroids.

In other aspects of the topical compositions described herein may be used in combination with other treatments, such as laser therapy, such as the pulsed dye laser; phototherapy, such as pulse therapy mixed light (photoderm), TDF pulses high intensivnogo light; photodynamic therapy, electrocoagulation, and opto-electronic interaction (ELOS); or electrosurgery.

Other medicines or treatments can be administered to the patient simultaneously or in a sequence and within a time interval of application of brimonidine, for example active ingredients or agents can act together for the treatment or prevention of telangiectasia and related symptoms. For example, another medication or treatment, brimonidine you can enter in the same or a separate structure at the same or at different times, i.e. before or after. Any suitable route of administration may be used to deliver additional treatment or medicines.

Another aspect of the invention relates to a method for producing a packaged product to ensure safe and effective treatment of telangiectasias or related symptoms to the patient. The method includes:

(1) preparation of topical compositions containing from about 0.3% to about 10% by weight of brimonidine and a pharmaceutically acceptable carrier;

(2) the development of guidelines for topical introduction of the topical composition to the skin area affected by telangiectasia or its symptoms, to achieve safe and effective treatment and

(3) the premises is their topical compositions and instructions in a single package, in which topical introduction leads to indicators of brimonidine in serum or plasma with a mean value of Cmaxapproximately 54±28 PG/ml or less and a mean AUC0-24happroximately 568±277 PG·h/ml or less.

In one embodiment of the invention, the topical composition is contained in one suitable container, such as a dropper, a Bank or a tube with a suitable outlet small in size, such as a tube with an elongated spout, made from any pharmaceutically suitable material. Topical compositions in accordance with the variants of the invention can be filled and Packed in legacimusic plastic bottle or tube. Proper packing/sealing for packaging of topical compositions according to the invention are commercially available, for example from Wheaton Plastic Products, 1101 Wheaton Avenue, Millville, N. J. 08332. In some cases, may be provided to the applicator tank, attached or separate from it.

In one of the embodiments of the invention, the instructions are, for example, a brochure or a label. Instructions explain how to apply the topical compositions according to the invention, in amounts and for a period of time sufficient to ensure safe and effective treatment of telangiectasias or related symptoms. Predpochtite is) instructions include, for example, the dosage and application instructions, the composition of the topical composition, clinical pharmacology, drug resistance, pharmacokinetics, absorption, bioavailability and contraindications.

In one variant of the invention, the topical composition is a topical composition in the form of a gel, which includes:

from approximately 0.3% (m/m) to approximately 10.0% (m/m) of brimonidine;

from approximately 0,20% (m/m) to about 4.0 percent (m/m) a gelling agent; and

from approximately 5.0 percent (m/m) to about 30.0 per cent (m/m) at least one polyol.

The composition of the topical application is obtained by mixing a pharmaceutically acceptable carrier with a safe and effective amount of brimonidine in accordance with well-known in this field of ways, for example by the methods provided by the standard link texts, such as REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 1577-1591, 1672-1673, 866-885 (Alfonso R. Gennaro ed. 19th ed. 1995); Ghosh, T. K.; et al. TRANSDERMAL AND TOPICAL DRUG DELIVERY SYSTEMS (1997), each of which is incorporated into the present application in its entirety by reference.

In a preferred variant of the invention, the topical composition in the form of gel contains from about 0.4% to about 0.6% by weight of brimonidine, more preferably 0.5% by mass of brimonidina that the waste.

Suitable gelling agents are known in this field, including those used in the gels of two-phase or single-phase system, can be used in the present invention. Some examples of suitable gelling agents are disclosed in REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY, 1517-1518 (Alfonso R. Gennaro ed. 19th ed. 1995), which is incorporated into the present application in its entirety by reference. Gelling agents used in the variants of implementation of the present invention include, but are not limited to, one or more hydrophilic and water-alcohol gelling agents used in the cosmetic and pharmaceutical industries. Preferably, the hydrophilic or hydroalcoholic gelling agent includes "CARBOPOL®" (B. F. Goodrich, Cleveland, Ohio), "HYPAN®" (Kingston Technologies, Dayton, N. J.), "NATROSOL®" (Aqualon, Wilmington, Del.), "KLUCEL®" (Aqualon, Wilmington, Del.) or "STABILEZE®" (ISP Technologies, Wayne, N. J.). The preferred percentage range of the weight of the composition for "CARBOPOL®" is from about 0.5% to about 2%, while the preferred percentage range of weight for "NATROLSOL®" and "KLUCEL®" is from about 0.5% to about 4%. The preferred percentage range of the weight of the composition and for "HYPAN®", and "STABILEZE®" is from 0.5% to about 4%. Other preferred gelling agents include hydroxyethyl cellulose cellulose gum, MVE/MA decadiene crosspolymer, PVM/MA copolymer, glycerin polyacrylate, or combinations thereof.

Examples of Carboneras, which can be used in the present invention include, but are not limited to, Carbomer 910, 934P, 940, 941, 980 and 1342, Carbopol® 974P and Carbopol® 980. Preferably, Carbonara is Carbomer 934P or Carbopol® 974P and Carbopol® 980.

According to variants of implementation of the present invention, the number of carbomer in the composition is about 0,5%, 0,6%, 0,7%, 0,8%, 0,85%, 0,95%, 1,05%, 1,15%, 1,25%, 1,35%, 1,45%, 1,5%, 1,6%, 1,7%, 1,8%, 1,9% or 2.0% (m/m).

The polyol composition in the form of a gel with various dissolved components used to minimize irritation when applied to the skin of the patient, while ensuring the bioavailability of the active substance in the preparation. Cm. Other III et al. "Gels and Jellies," pp. 1327-1344 of Encyclopedia of Pharmaceutical Technology, vol. 3 (ed. by Swarbrick, et al., pub. by Marcel Dekker, 2002); or Pena, "Gel Dosage Forms: Theory, Formulation, and Processing", pp. 381-388 of Topical Drug Delivery Formulations (ed. by Osborne et al., pub. by Marcel Dekker, Inc., 1990). The polyols in the composition in the form of a gel can serve one or more functions, such as solubilizing agent, humectant, emollient substances, skin moisturizer, agent, penetrating through the skin, etc., Suitable polyols that may be used in embodiments implementing the present invention, include, but are not limited to, glycerin, propylenglycol is, dipropyleneglycol, hexyleneglycol, butyleneglycol and liquid polyethylene glycols, such as polyethylene glycol 200-600.

According to variants of implementation of the present invention, the total amount of the polyols in the composition is from about 5.0 percent to 30.0% (m/m), for example approximately 5,0%, 5,5%, 6,0%, 6,5%, 7,0%, 7,5%, 8,0%, 8,5%, 9,0%, 9,5%, 10,0%, 10,5%, 11,0%, 11,5%, 12,0%, 12,5%, 13,0%, 13,5%, 14,0%, 14,5%, 15,0%, 17%, 20%, 25% or 30% (m/m).

Preferably, the topical composition in the form of a gel containing the first polyol and the second polyol, such as propylene glycol and glycerol, respectively.

According to variants of implementation of the present invention, the amount of each of the first and second polyols in the composition is independently from about 4 to 15%, in particular from 4.5% to 6.5% (m/m), for example 4,5%, 5,0%, 5,5%, 6,0% and 6.5% (m/m).

The pH value for the topical compositions according to the invention preferably in accordance with a physiologically acceptable pH value, for example in the range from 4 to 8, preferably from about 6 to about 7.5, and more preferably from about 4.5 to about 6.5. To stabilize the pH, preferably include an effective amount of a buffer. In one embodiment of the invention, the buffer agent is present in an aqueous topical composition in an amount of from about 0.05 to about 1 percent of the mass of the drug.

Topice the Kai composition in the form of a gel according to the present invention may include one or more of the other components, such as a protective agent, a cosmetic agent, absorbent, preservative, antioxidant, surfactant, agent, penetrating through the skin, local anesthetics, analgesics, etc.

In a preferred variant of the invention, the topical composition in the form of a gel in accordance with a variant embodiment of the invention further includes dispersible in water to form titanium dioxide (TiO2), preferably in a quantity sufficient to hide the color of brimonidine or other color component in the composition, but without causing skin irritation. TiO2may cause slight irritation and redness of the eyes, thus, avoid contact with eyes TiO2-containing compositions of topical application. Titanium dioxide gives white the topical composition is applied and increases opacity and lack of transparency of the composition. Titanium dioxide absorbs, reflects or scatters light (including ultraviolet radiation in the light), which can help to protect the products from damage. Titanium dioxide can also be used as a sunscreen to protect you from the harmful effects of ultraviolet radiation, which is part of the sunlight.

According to variants of the implementation of this izaberete the Oia, the number of water-dispersed form of titanium dioxide in the composition is approximately from 0.04 to 0.2%, in particular 0,04%, 0,0425%, 0,0525%, 0,0625%, 0,0725%, 0,0825%, 0,09%, 0,10%, 0,15% or 0.20% (m/m).

Suitable preservatives include, but are not limited to, Quaternary ammonium compounds such as benzalkonium chloride, benzene chloride, cetrimide, decaline chloride and cetylpyridinium chloride; alcoholic agents, for example chlorobutanol, phenethyl alcohol and benzyl alcohol; parabens, such as methylparaben, ethylparaben, propylparaben, and butylparaben; antibacterial esters, for example esters of hydroxybenzoic acid; and other antimicrobial agents such as chlorhexidine, chlorocresol, benzoic acid, polymyxin and Phenoxyethanol. Preferably, the preservative is selected from the group consisting of sodium benzoate, Phenoxyethanol, benzyl alcohol, methylparaben, imidazolidinedione and thiazolidinedione.

In addition to brimonidine, the composition for topical application in accordance with a variant embodiment of the invention may optionally include one or more other pharmaceutically active ingredients, including, but not limited to, medications used to treat the underlying disease, which is caused by telangiectasia, antihistamines to control itching, antibiotics, corticoste oidy, intravenous immunoglobulin, acetaminophen, etc.

This invention will be better understood with reference to the following non-limiting examples, the person skilled in the art will easily understand that the examples are only illustrative of the invention, which are described in more detail in the claims, following after them.

Example 1

Topical compositions in the form of a gel

This example displays the topical compositions in the form of a gel, which can be used in the present invention.

The first group of compositions in the form of a gel is described below in table 1.

Table 1
Components% (m/m)% (m/m)% (m/m)
Brimonidine tartrate0,3-0,6%0.6 to 3%3-10%
Methylparaben NF0,15%0,20%0,10%
Propylparaben NF0,03%0,02%0,04%
The hydroxyethyl cellulose NF 1,0%1,25%1,5%
Butyleneglycol 1,33,0%6,0%18,0%
Glycerin2,0%4,0%12,0%
Dimitriades USP0,05%0, 05%0,05%
Purified water, USPEnoughEnoughEnough
TOTAL100%100%100%

The pH value of the composition was adjusted to approximately 4,5-7,0.

The second group of compositions in the form of a gel is described below in table 2.

Table 2
Components% (m/m)% (m/m)% (m/m)
Brimonidine tartrate0,3-0,6%0,6-3,0% 3,0-10%
Methylparaben0,20%0,20%0,20%
Propylparaben0,05%0,05%0,05%
KLUCEL®2,0%2,5%1,0%
Propylene glycol3%6%15%
Glycerin, USP3%6%15%
10% of titanium dioxide0,5%0,6%0,7%
Purified water, USPEnoughEnoughEnough
TOTAL100%100%100%

The ingredients are mixed and to the mixture is added slowly an aqueous solution of sodium hydroxide to achieve a pH from about 4.5 to 6.5 and gel formation.

The third is the group of compounds in the form of a gel is described below in table 3.

Table 3
Component% (m/m)% (m/m)% (m/m)
Brimonidine tartrate0,3-0,6%0,6-3,0%3,0-10%
Carbomer 934P1,25%1,0%1,5%
Methylparaben0,2%0,15%0,20%
Phenoxyethanol0,4%0,35%0,4%
Glycerin5,5%10%15%
Kowet titanium dioxide0,0625%0,0725%0,0825%
Propylene glycol5,5%10%15%
Distilled waterSufficient if esto EnoughEnough
TOTAL100%100%100%

The components are mixed and to the mixture is added slowly an aqueous solution of sodium hydroxide to a pH of from about 4.5 to 6.5 and gel formation.

The fourth group of compounds in the form of a gel is described below in table 4.

Table 4
Component% (m/m)% (m/m)% (m/m)
Brimonidine tartrate0,3-0,6%0,6-3,0%3,0-10%
Methylparaben0,15%0,125%0,1%
Propylparaben0,05%0,05%0,06%
The carbopol®9801,0%0,8%1,5%
Glycerin5,5% 10%15%
10% of titanium dioxide0,575%0,675%0,775%
Propylene glycol4,5%8%12%
WaterEnoughEnoughEnough
TOTAL100%100%100%

The components are mixed and stirred. Triethanolamine is added to achieve a pH from about 5.5 to 7.0.

Example 2

A comparative study of the bioavailability and pharmacokinetics of the compositions of brimonidine

This study was randomized conducted using blind estimation method, inside individual comparative pharmacokinetic study in which brimonidine tartrate, ophthalmic solution (0.2%) and topical gel (0.07 per cent, of 0.18% and 0.50%) was used under conditions of maximum use during the 29 days in patients with moderate and severe form of erythema associated with rosacea. Jus the e entrance criteria included a clinical diagnosis of moderate to severe erythema of the face, associated with rosacea, CEA score ≥3 and IOP 11-21 mm RT. Art. Conducted intra-subject comparison of topical and ophthalmic effects after one day of treatment with 0.2% ophthalmic solution brimonidine tartrate.

In total, there were randomized 102 patients: 24, 26, 25 and 27 patients in the 0.5% gel QD, 0.18% gel BID 0.18% gel QD and 0.07% gel BID accordingly. On the 1st day of the visit, one drop of 0.2% ophthalmic solution brimonidine tartrate was administered in each eye every 8 hours during a 24-hour period. After a 2-day washout period one gram of topical gel (0.07 per cent, of 0.18% or 0.50% of brimonidine tartrate) was applied once (QD) or twice (BID) daily on behalf of patients within 4 weeks.

Blood samples for full profiling PK were made during the 24-hour eye exposure (day 1) and on the first day topical application (day 4), on the fifteenth day after topical application (day 18) and after the last topical application to 72 hours after a dose (day 32). Additional blood samples were collected before application (day 10, day 24). The concentration of brimonidine in plasma was determined using the method of determining the LC-MS/MS with a lower limit of quantitation (LOQ) of 10 PG/ml.

PK parameters for brimonidine were calculated using standard compartmental method, and Csub> maxAUC0-24hstatistically analyzed using log-transformed data. Both were carried out reverse exponential transformation of the differences between time of application and between the experimental groups, the boundaries of the intervals to obtain the 90% confidence intervals (90% CI) of the ratio of geometric means on the original scale. Statistical analysis was performed using all Cmax(BLQ values are replaced LOQ) and using only quantitative AUC0-24h.

PK results showed that:

(1) Eye application: application of 0.2% of brimonidine tartrate ophthalmic caused by the impact, quantifiable (>10 PG/ml) all patients received treatment with TID. Pharmacokinetic (PK) parameters ophthalmic solution have an average value of Cmaxfrom 54±28 PG/ml (range: 16-134 PG/ml), and the average AUC0-24h568±277 PG·h/ml (range: 124-1490 PG·h/ml). This was consistent with the known from the prior art of 0.2% (m/m) ophthalmic solution brimonidine tartrate, for example NDA:21-262, 0.2% of brimonidine of purita multiple doses, Cmax65±38 PG/ml

(2) Topical application: daily topical application of the gel brimonidina within 29 days resulted in quantitative (>10 PG/ml) systemic effects of 24%, 4%, 68% and 75% of patients receiving gel brimonidina 0,07% BID 0,18% QD, 0.18% of BID or 0.5% QD, respectively. At the end of the period of exposure mean (±SD) value of Cmaxwas 13±9 PG/ml, 17±20 PG/ml, 17±10 PG/ml, 25±24 PG/ml for gel brimonidina 0,07% BID 0,18% QD, 0.18% of BID or 0.5% QD, respectively. Defined quantitatively the value of AUC0-24hwas 172±87 PG·h/ml, 183±113 PG·h/ml, 267±119 PG·h/ml, 364±216 PG·h/ml for gel brimonidina 0,07% BID 0,18% QD, 0.18% of BID or 0.5% QD, respectively.

The effect of multiple doses of gel brimonidina on pharmacokinetic parameters (duration: day 4/day 18/day 32) was estimated for each group topical application. Exposure on the first day topical application is comparable to that observed after 29 days of topical application in all groups, indicating no accumulation of the drug throughout the duration of exposure (i.e., 4 weeks) regardless of the dose and dosage regimen. Regardless of dose and mode of testing eye/topical value, calculated over the entire period of topical exposure (day 4, day 18 and day 32), was significantly less than 1.

After topical application of the gel brimonidina systemic exposure was increased with the addition of dose. However, statistical analysis showed that the systemic exposure (Cmax) not p is oportional dosage. The average value of Cmaxincreased less than proportional dosing.

Topical systemic exposure (expressed in Cmaxor AUC0-24h) on the surface of the skin compared with figures obtained after ocular application. Cm. table 5.

Table 5
Statistical comparison of the ocular and topical exposure
CD07805/47 Gel 0.5% of QD Estimate (90% CI)CD07805/47 Gel 0,18% BID Estimate (90% CI)CD07805/47 Gel 0,18% QD Estimate (90% CI)CD07805/47 Gel 0,07% BID Estimate (90% CI)
Cmax
The ratio between topical introduction to the day of the visit and day 1 (ophthalmic introduction)
Day 4/day 10,3 (0,3, 0,3)0,3 (0,2, 0,3)0,2 (0,2, 0,3)0,2 (0,2, 0,2)
Day 18/day 10,6 (0,5, 0,7)0,3 (0,3, 0,4)0,2 (0,2, 0,3) 0,2 (0,2, 0,2)
Day 32/day 10,4 (0,3, 0,4)0,3 (0,3, 0,4)0,3 (0,2, 0,3)0,2 (0,2, 0,3)
Quantitative AUC0-24h
The ratio between topical introduction to the day of the visit and day 1 (ophthalmic introduction)
Day 4/day 10,6 (0,4 and 0,7)0,4 (0,3, 0,5)0,3 (0,2, 0,4)0,1 (0,1, 0,3)*
Day 18/day 1of 0.7 or 0.6, and 0.9)0,5 (0,4, 0,6)0,3 (0,2, 0,4)0,5 (0,2, 0,8)*
Day 32/day 10,5 (0,4 and 0,7)0,5 (0,4, 0,6)0,3 (0,2, 0,4)0,4 (0,3, 0,7)*
(a) should be taken with caution due to the limited number of quantitative AUC0-24h(2 to 6)
N. B.: day 4 → the first topical application; day 18 → OE topical application; den is 32 → 29th and the last topical application.

In all tested doses and dosing schedules of eye/topical ratio calculated for the entire period of topical application (day 4, day 18 and day 32), was significantly lower than 1. The average value of Cmaxwas 0.2 to 0.07 per cent BID group, in the range from 0.2 to 0.3 for the 0.18% QD and BID groups and in the range from 0.3 to 0.6 to 0.5% QD group. For values of Cmaxthe upper limit of the 90% confidence interval does not include 0,8, regardless of the tested dosage and dosage regimen. The highest ratio was observed in 0.5% QD group (average coefficient of 0.6, 90% CI [0,5-0,7]) 15 days after application, but was not confirmed at the end of the 29-day topical exposure (average coefficient of 0.4, 90% CI [0.3 to 0.4]). The same trend was observed with quantitative AUC0-24h. The results of clinical studies have shown that systemic exposure obtained after topical application of all concentrations and test modes in the study was significantly lower compared to the systemic exposure resulting from the application of eye drops used in accordance with the recommendations on the label ophthalmic products.

In conclusion, the calculated pharmacokinetic parameters (at least Cmax) was observed in all experimental groups. It was found that the bore is of atra on the increase in systemic exposure with the use of doses of brimonidine, statistical analysis showed that the increase in systemic exposure (Cmax) is not proportional to the dosage, for example, increasing the average value of Cmaxit was much smaller than the increase in dose. No evidence of systemic accumulation was not observed.

All estimated concentrations and schemes were well-tolerated and safe. There have been no clinically significant reductions in the mean values of IOP, vital or routine laboratory parameters in any of the groups affected by the topical gel. The increase in the concentration of the drug or schema test had no effect on the incidence of cardiac/vascular side effects. Communication between any of the pharmacokinetic parameters and severity of any side effects associated with topical gel, is not detected. In the period of exposure topical gel applied to the skin (day 4 to the end of the study), there have been no serious adverse events (laid off). Two laid off were registered during the period of exposure eye connection (days 1-3) in two patients, one laid off (acute hypotension) is associated with the ophthalmic solution. Both patients with the REMOVAL were excluded from the study prior to any effects of topical gel.

The results showed that the system is mnoe impact obtained after topical application to affected areas of skin in all tested concentrations of brimonidine and schemes tested, significantly lower compared to the systemic exposure obtained from eye drops (0.2 percent by weight of brimonidine tartrate) used in accordance with the recommendations on the label ophthalmic products.

Based on this comparative study of the bioavailability and pharmacokinetics, concentration of brimonidine above 0.2% (m/m) can be used for topical application on the affected area of the skin for the safe and effective treatment of skin diseases.

Example 3

Clinical study of the composition of brimonidine in the form of a gel

Clinical study

Single dose, randomized, placebo-controlled study to establish dose conducted using double-blind methods in parallel groups, was conducted to evaluate the pharmacodynamics and safety of three gel formulations containing three concentrations of brimonidine tartrate, i.e., 0.07 per cent, of 0.18% and 0.50% by weight, in patients with stable, moderate to severe erythema associated with eritematoso-teleangiectasias rosacea.

In total, 122 patients were randomized to apply one of the three topical formulations in the form of a CGU is I (N=31, N=31, N=28 for 0.5%, 0.18%, the 0.07 per cent, respectively) or placebo gel (N=32). A single application was made to face in the morning. After the application of patients were left on the place of study on mandatory 12-hour observation period after administration of the dose. All 122 patients completed the study and were numbered among the patients who took at least one dose, and to sample for safety assessment. A total of 117 patients (96%) were assigned to the population sample.

Telangiectasias each patient was evaluated on a scale from 0 to 4 according to the General assessment system telangiectasia (TGA), where 0 means that there is no sign of telangiectasias, and 4 means severe telangiectasia, with many clearly visible telangiectasia. Evaluation of TGA was recorded in the pre-treatment or pre-dosing and at various times after application.

Changes in estimates of the TGA were analyzed using analysis of covariance model (ANCOVA) with the center of analysis, processing factors and the relevant underlying value as of covariate.

Efficacy

Table 6 summarizes the average changes and average minimum (min) and maximum (max) changes TGA from its initial state to its introduction during the 12-hour interval. Effect of 0.5% (m/m) of brimonidine led to a greater reduction TGA comparedwith placebo or a lower concentration of brimonidine, for example 0.18% (m/m) or 0.07% (m/m).

Table 6
Average changes TGA from the beginning of introduction
0.5% of brimonidine (N=31)0,18% of brimonidine (N=31)0,07% of brimonidine (N=28)Placebo
(N=32)
The average change-0,28-0,16-0,210,03
Average min, max change-2,4, 1,5-1,7, 0,5-1,7, 0,1-1,7, 0,9

In addition, as shown in Fig.1-6, a significant reduction in telangiectasia observed in the treatment with 0.5% (m/m) brimonidina, for example, 30 minutes after application, which continued even after 12 hours after application.

More effective and lasting treatment of telangiectasias of 0.5% (m/m) brimonidina observed in a clinical study, is unexpected in light of the ophthalmic applications of brimonidine, where an increase in the concentration of brimonidine does not lead to significant efficiency gains, and a decrease in the concentration of Rimondi is a, for example up to 0.1% (m/m), retains its effectiveness in the reduction of IOP.

Security application

Intraocular pressure (IOP) was measured before the application (T0) and at 12 noon on the day of application. A slight decrease was observed in all experimental groups. However, there is no clear pattern associated with the ability to determine the dose level by brimonidina. The results show that topical application of elevated up to 0.5% (m/m) concentrations of brimonidine on the skin area affected by telangiectasia, will not increase the effect on IOP.

No serious side effects (PPA) and no adverse reactions (AR), leading to the termination of the study, was not observed. Some NYA comparable between groups. With the increase in doses increasing the number NYA was not. Unwanted side effects associated with the drug were observed.

Unlike ophthalmic applications of brimonidine, where prolonged use of low concentrations of brimonidine, such as 0.1% (m/m), provides improved portability while maintaining efficiency reduction of IOP, in the present clinical study unexpectedly found that higher concentrations of brimonidine provide significantly improved clinical efficacy in the treatment of telangiectasias or related proc is Ohm, without causing any significant changes in the field of patient safety and tolerability compared with lower concentrations of brimonidine.

Specialists in this field will understand that there may be changes in the above-described ways without deviating from the latitude inventive concept. It is clear that the invention is not limited to specific variants of its implementation, but it is intended to cover modifications within the essence and scope of the present invention, as defined in the claims.

1. How safe and effective treatment of telangiectasias or symptoms associated with it, in a patient, comprising the topical application to the skin area affected by telangiectasia or symptom, topical compositions containing from about 0.4% to about 0.6% by weight of brimonidine and a pharmaceutically acceptable carrier, where the topical introduction leads to indicators of brimonidine in serum or plasma with a mean value of Cmaxabout 54±28 PG/ml or less and a mean AUC0-24habout 568±277 PG·h/ml or less.

2. The method according to p. 1, in which the telangiectasia telangiectasia is associated at least with age, sun, alcohol, scleroderma, hereditary hemorrhagic telangiectasia (Bo what esnu Randy-Osler-Weber), ataxia-telangiectasia, spider hemangioma, congenital telangiectatica marble skin syndrome bloom syndrome Klippel-Crinone-Weber disease (Sterga-Weber, pigment xeroderma, flaming nevus, generalized telangiectasia of unclear etiology (GET), serpiginosa the angioma, ataxia-telangiectasia, spider nevus, CREST syndrome, hereditary hemorrhagic telangiectasia (a disease of Rendu-Weber-Osler), ataxia-telangiectasia, basal cell with epitheliomas, scleroderma, unilateral nevodnoi the telangiectasia and congenital telangiectatica marble skin.

3. The method according to p. 1, in which the telangiectasia telangiectasia is formed in the result of rosacea.

4. The method according to p. 1, in which the symptoms associated with telangiectasia selected from the group consisting of swollen blood vessels, enlarged, varicose veins and/or visible spider veins and red, purple or blue skin, resulting expansion of the blood vessels associated with telangiectasia.

5. The method according to p. 1, wherein the topical composition is applied to the skin daily once a day.

6. The method according to p. 1, which additionally comprises applying to a patient at least one additional drug cf is DSTV or active agent for the treatment of telangiectasias or associated symptoms.

7. The method according to p. 6, in which additional active agent selected from the group consisting of iselevoi acid, benzoyl peroxide, isotretinoin, antibiotics, their pharmaceutically acceptable salts and combinations.

8. The method according to p. 1, in which the topical composition further includes:
from approximately 0,20% (m/m) to about 4.0 percent (m/m) a gelling agent; and
from approximately 5.0 percent (m/m) to about 30.0 per cent (m/m) at least one polyol.

9. The method according to p. 8, in which the topical composition comprises from about 0.4% to about 0.6% by weight of brimonidine tartrate.

10. The method according to p. 9, in which the topical composition comprises about 0.5% by weight of brimonidine tartrate.

11. The method according to p. 8, in which the topical composition comprises from about 0.50% (m/m) to approximately 2.0% (m/m) carbomer.

12. The method according to p. 8, in which the topical composition further comprises from about 0.04 percent (m/m) to approximately 0,08% (m/m) dispersible in water to form titanium dioxide.

13. The method according to p. 8, in which the topical composition further comprises a preservative selected from the group consisting of sodium benzoate, Phenoxyethanol, benzyl alcohol, methylparaben, imidazolidinedione and thiazolidinedione.

14. The method according to p. 8, in which the topical composition contains at m is d one glycerol and propylene glycol.

15. The method according to p. 8, in which the topical composition comprises at least one glycerol and propylene glycol.

16. The method of obtaining the Packed product to ensure safe and effective treatment of telangiectasias or related symptoms in a patient, including:
(1) preparation of topical compositions containing from about 0.4% to about 0.6% by weight of brimonidine and a pharmaceutically acceptable carrier;
(2) the development of guidelines for topical introduction of the topical composition to the skin area affected by telangiectasia or symptoms to obtain a safe and effective treatment and
(3) the location of topical compositions and instructions in a single package, in which topical introduction leads to indicators of brimonidine in serum or plasma with a mean value of Cmaxabout 54±28 PG/ml or less and a mean AUC0-24habout 568±277 PG·h/ml or less.

17. The method according to p. 16, in which the topical composition comprises:
from about 0.4% (m/m) to approximately 0.6% (m/m) of brimonidine;
from approximately 0,20% (m/m) to about 4.0 percent (m/m) a gelling agent; and
from approximately 5.0 percent (m/m) to about 30.0 per cent (m/m) at least one polyol.

18. The method according to p. 17, in which the topical composition comprises from about 0.4% to about 0.6% by weight of Rimondi is and tartrate.

19. The method according to p. 17, in which the topical composition comprises about 0.5% by weight of brimonidine tartrate.

20. The method according to p. 17, in which the topical composition is in the form of gel contains from about 0.50% (m/m) to approximately 2.0% (m/m) carbomer and at least one glycerol and propylene glycol.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the pharmaceutical industry and represents a composition for treating acne, rosacea and hyperpigmentation, in the form of a gel which contains anchoic acid, a hydrophobic ingredient, a non-aqueous solvent, an emulsifying agent, a gel-forming polymer, a preserving agent, a pH control agent and additionally methylpyrrolidone with anchoic acid having a particle size of less than 100 mcm, while anchoic acid is related to methylpyrrolidone as 1:0.025 to 1:4.

EFFECT: invention provides easy penetration of anchoic acid through a horny layer and its resolution into the oil grand ducts and between skin cells, providing high concentration of anchoic acid that promotes better antibacterial, keratolytic and de-pigmentation effects.

5 cl, 2 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to a compound of Formula

,

where Y represents a group of formula -(CR9R10)-; X is selected from the group, consisting of -C(=O)-, -OC(=O)-, -NHC(=O)-, -(CR11R12)- and -S(-O)2-; Z represents a group of formula -(CR13R14)q-; R1 is selected from the group, consisting of C1-C12alkyl, optionally substituted with one substituent, selected from naphthyl, indole and biphenyl; C2-C12alkenyl, substituted with a substituent, selected from thienyl, naphthyl and phenyl, with the said phenyl being optionally substituted with 1-2 substituents; selected from halogen, trifluoroalkyl, C1-C6alkyl, methoxy and hydroxy; C3-C6cycloalkyl; C6-C10aryl, optionally substituted with 1-2 substituents, selected from halogen, phenyl, amino, phenoxy, C1-C6alkyl, methoxy, hydroxyl and carboxy; and C4-C9heteroaryl, selected from indole, quinoline, quinoxaline, benzofuranyl, benzothiophene, benzimidazole, benzotriazole, benzodioxin, benzothiasole, pyrazole, furyl and isoxazole, optionally substituted with a substituent, selected from C1-C6alkyl and phenyl; R2 and R3 each is independently selected from the group, consisting of H and C1-C12alkyl; R4a is selected from the group, consisting of H, C1-C12alkyl, optionally substituted with phenyl; C2-C12alkenyl, C3-C6cycloalkyl, C6aryl, C(=O)R15, C(=O)NR15R16, C(=O)OR15, SO2R15 and -C(=NR15)-NR16R17; R4d represents hydrogen or R4a and R4b, taken together with a nitrogen atom, which they are bound to, form an optionally substituted heterocyclic fragment, selected from piperidine, morpholine, pyrrolidine and azetidine, where the substituent is selected from C1-C12alkyl, hydroxy, halogen, carboxy and oxo; each R5a and R5b represents H, or R6, R7 and R8 each is independently selected from the group, consisting of H, C1-C12alkyl, C3-C6cycloalkyl, C6-C10aryl, optionally substituted with halogen, or taken together with a carbon atom, which they are bound to, two or more of R6, R7 and R8 form a fragment, selected from the group, consisting of C2-C12alkenyl; C3-C6cycloalkyl, optionally substituted with C1-C6alkyl; C6aryl, optionally substituted with 2 substituents, selected from halogen; each R9 and R10 represents H or C1-C12alkyl, substituted with naphthyl; each R11 and R12 represents H; R13 and R14 represent H, or each R15, R16 and R17 is independently selected from the group, consisting of H, C1-C12alkyl, C3-C6cycloalkyl, C6aryl, substituted with one substituent, selected from C1-C6alkyl; and C5-heteroaryl, additionally containing one nitrogen atom, with the said heteroaryl representing pyridyl; q represents an integer number, selected from the group, consisting of 2, 3 and 4; r represents 1; or its pharmaceutically acceptable salt. The invention also relates to particular compounds of 1,4-diazepan-2-one derivatives.

EFFECT: obtaining 3-aminoalkyl-1,4-diazepan-2-one melanocortin-5 receptor antagonists.

21 cl, 7 tbl, 110 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to dermatology, and can be used for selecting a therapeutic approach to acne in females by examining biological fluids and prescribing preparations depending on the clinical findings. The biological fluids are blood and urine; blood serum hormones and steroid urine profile are tested, and the derived values are compared to the standard norms specific for the absence of acne, while the preparations are prescribed according to the comparison results. Specifically, if observing an increase of blood luteinising hormone up to 16 mIU/ml, testosterone up to 4 ng/ml, an increase of urine androsterone up to 20 mcmole/24 hours, etiocholanolone up to 11 mcmole/24 hours, total 17-ketosteroids up to 35 mcmole/24 hours, van de Calseyde's discriminant up to 3, the combined oral contraceptive Jess with the anti-androgenic effect. If also observing an increase of immunoreactive protein up to 12.90 mcUnit/ml and insulin-line growth factor 1 up to 361.04 ng/ml, the combined oral contraceptive Jess and Metformine or Metformine are prescribed. If observing a decrease of blood oestradiol up to 140 pmole/l or an increase of the concentration of luteinising hormone up to 7 mIU/ml, dihydroepiandrosterone sulphate up to 4 mmole/l, 17 - hydroxyprogesterone up to 4 nmole/l and testosterone up to 4 nmole/l in blood and an increase of urine androsterone up to 17 mcmole/24 hours, etiocholanolone up to 17 mcmole/24 hours, 11 - ketoandrosterone up to 2.5 mcmole/24 hours, 11 - ketoetiocholanolone up to 2.5 mcmole/24 hours, 17 - ketosteroids up to 50 mcmole/24 hours and van de Calseyde's discriminant up to 3, the glucocorticoid Metypred is prescribed. The high blood concentration of luteinising hormone up to 15 mIU/ml, dihydroepiandrosterone sulphate up to 6.82 mcmole/l, 17 - hydroxyprogesterone up to 4 nmole/l and an increase of urine androsterone up to 19.5 mcmole/24 hours, etiocholanolone up to 16 mcmole/24 hours, dihydroepiandrosterone up to 7 mcmole/24 hours, 17 - ketosteroids up to 45 mcmole/24 hours and van de Calseyde's discriminant up to 3.5 enables using the combined oral contraceptive Jess and the glucocorticoid Metypred. And the preparation Dostinex is prescribed in observing the above values in a combination with an increase of blood prolactin up to 750 IU/ml and a decrease of blood oestradiol up to 95.48 pcg/ml.

EFFECT: method enables providing higher therapeutic selectivity and clinical effectiveness in acne without the need of thorough examination to be conducted.

4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmaceutics, in particular represents composition for topic application, which includes, into physiologically acceptable medium at least one derivative of naphthoic acid, benzoylperoxide and at least one film-forming component.

EFFECT: invention is characterised by the fact that said compound of naphthoic acid and benzoylperoxide are in dispersed in said composition form.

23 cl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an herbal formulation of topical nanoemulsion for treating acne-related skin disorders. The above formulation contains an aqueous phase comprising a therapeutic agent, rose water and/or lemon juice, and an oil phase containing an essential oil, a non-ionic surfactant and an accessory surfactant. The aqueous and oil phases are related within the range of 1:1 to 1:2, while a particle size of the herbal formulation is less than 5 nm. The essential oil is presented by tea tree oil, basil oil, rosemary oil, lavender oil, jojoba oil, bergamot oil, clove oil and peppermint oil. The invention also refers to a method for preparing the herbal formulation which involves providing the aqueous and oil phases, mixing the above phases to produce a mixture to be emulsified with the non-ionic surfactant to prepare a macroemulsion. The prepared macroemulsion is mixed with ethanol to produce a nanoemulsion with a particle size less than 5 nm.

EFFECT: invention provides the herbal formulation with good penetration, prolonged effect causing no irritation.

8 cl, 4 dwg, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of the following formula , in which n equals integer number from 1 to 15, m equals 0, 1, 2 or 3, and R represents hydrocarbon chain of polyunsaturated fatty acid, selected from omega-3 and omega-6 polyunsaturated fatty acids, and to method of obtaining them.

EFFECT: development of pharmaceutical or cosmetic composition based on said compounds and to method of acne or seborrheic dermatitis treatment for cosmetic purposes.

16 cl, 4 dwg, 2 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to a compound of formula (I)

where Y represents a group of formula -(CR9R10)n-; X represents -C(=O)-; Z represents a group of formula -(CR13R14)q-; R1 is selected from a group, consisting of (a) C2-C12alkenyl, substituted with 4-chlorophenyl; or (b) C6-C10aryl, optionally substituted with one or two halogen atoms; R2 and R3 represent H; R4 is selected from a group, consisting of H, C1-C12alkyl, optionally substituted with hydroxyl, methoxy or benzyloxy, C3-C12cycloalkyl, C6aryl, optionally substituted with an amino group or pyperidine, C-bound C1-C18heteroaryl, selected from pyridine and imidazole, C(=O)R15, C(=O)NR16R17 and ONR16C(=NR17)NR18R19; each R5a and R5b represents H, each R6, R7 and R8 is independently selected from a group, consisting of H, C1-C12alkyl and C6-C18aryl, each R9 and R10 represents H; each R13 and R14 represents H; R15 represents H, each R16, R17, R18, R19 and R20 is independently selected from a group, consisting of H, C1-C12alkyl, C3-C12cycloalkyl, C6aryl and pyridyl, or any two of R16, R17, taken together with atoms, to which they are bound, form a cyclic group, containing 5 carbon atoms, or n equals to 1; q represents an integer number, selected from a group, consisting of 1, 2, 3, 4 and 5; r equals to 1; or its pharmaceutically acceptable salt.

EFFECT: invention relates to a pharmaceutical composition for treatment of MC5R-associated conditions, which contains a formula (I) compound and a pharmaceutically acceptable carrier, a diluent or a filling agent.

23 cl, 6 tbl, 53 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to pharmaceutical industry, in particular to a composition, possessing immunomodulating and anti-inflammatory properties. The dermatological composition, possessing immunomodulating and anti-inflammatory properties, as an active ingredient, contains an extract of the aboveground part/parts of oat, collected before ear formation. The cosmetic composition, possessing immunomodulating and anti-inflammatory properties. Application of the extract of the aboveground part/parts of oat, collected before ear formation, possessing immunomodulating and anti-inflammatory properties, as a medication.

EFFECT: composition and extract possess expressed immunomodulating and anti-inflammatory properties.

15 cl, 1 tbl, 3 ex

FIELD: medicine.

SUBSTANCE: invention refers to cosmetic industry and represents a non-foaming cosmetic composition of an oil-in-water emulsion containing (i) retinol, (ii) at least one polar emollient specified in a group consisting of propylene glycol stearyl ester, propylene glycol isostearate and mixtures thereof (iii) at least one non-polar emollient specified in a group consisting of aromatic or linear esters, Gerbe ester, mineral oils, squalane, isohexadecane, squalene, liquid paraffin and mixtures thereof with the weight ratio of the above polar emollient and the above non-polar emollient is found within the range of approximately 95 to 5 to approximately 40 to 60.

EFFECT: provided considerable reduction of retinoid-caused skin irritation and higher efficacy or retinoid.

11 cl, 3 ex, 7 tbl, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely a method of treating acne. The method of treating acne by prescribing line seed oil 10 ml 2 times a day, sodium selenite 90 mcg 1 time a day, tocopherol acetate 100 mg 2 times a day for 1 month.

EFFECT: method of treating acne is effective and enables reducing the length of treatment.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a pharmaceutical composition for treating type 2 diabetes, which contains (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)-butyryl]-3-trifluoromethyl-,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester or its pharmaceutically acceptable salt, metformin or its salt, and additive agents. Also, the invention refers to a method of treating type 2 diabetes involving administering the above pharmaceutical composition.

EFFECT: invention possesses the high efficacy of treating type 2 diabetes and lower toxicity than the known analogues.

21 cl, 8 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new compounds of formula I or their pharmaceutically acceptable salts, wherein R1 means phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen or 5-6-merous heteroaryl; R2 is phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen, halogen-C1-6alkyl, halogen-C1-6alkoxy, C1-6 alkylsulphonyl, nitrile, etc. R3 means H or C1-6 alkyl; X - -O-, -NRa-,-S(O)m- or CRbRc, wherein Ra - H, C1-6 alkyl or C1-6 alkylcarbonyl; Rb and Rc mean H or together with the atom to which they are attached, form 5-merous cycle additionally containing 2 oxygen atoms; m is equal to 0-2; Y means -NRc-, wherein Rc - H or C1-6 alkyl.

EFFECT: compounds can find application in medicine for treating autoimmune and inflammatory diseases related to P2X7 purinoceptor.

15 cl, 1 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to quinoxaline derivatives of general formula

,

a based pharmaceutical composition, using them as therapeutic agents, as well as to a based therapeutic agent for treating tumour diseases. In general formula I X represents: oxygen or sulphur; R1 represents hydrogen, R2/R3 represents hydrogen, R4 represents: (i) C1-C12-alkyl, (ii) saturated C3-C8-cycloalkyl, optionally substituted by C6-aryl, (iii) unsaturated C3-C8-cycloalkyl, (iv) heterocyclyl substituted by C(O)CF3, (v) C1-C6-alkyl substituted by C6-aryl, the above C6-aryl can be substituted by F, Cl, Br, I, -O-C1-C6-alkyl, C1-C6-alkyl, C6-aryl or hydroxy, (vi) C1-C6-alkyl substituted by C5-heteroaryl, (vii) C1-C8-alkylene, (viii) 1-adamantyl, (ix) C1-C6-alkyl substituted by C6-heterocyclyl containing a nitrogen atom and an oxygen atom, (x) C1-C6-alkyl substituted by C3-C6-cycloalkyl, or (xi) C1-C6-alkyl substituted by C6-heteroaryl; R5 represents hydrogen, R6 represents (i) aryl optionally substituted by C1-C6-alkyl, -O-C1-C6-alkyl, hydroxy, F, Cl, Br, I or amino, or (ii) C5-heteroaryl containing 2 nitrogen atoms optionally substituted by C1-C6-alkyl, R7 and R8 represent hydrogen.

EFFECT: producing the therapeutic agent for treating the tumour diseases.

7 cl, 3 tbl, 5 ex

FIELD: medicine.

SUBSTANCE: group of inventions refers to medicine, namely to dermatology, and can be used for treating such diseases, as rosacea, psoriasis, topic dermatitis or acne. That is ensured by a local application on an individual's skin area of a topical composition, which can be an ingredient of a kit and contains a therapeutically effective amount of an α2-adrenergic receptor agonist, wherein the α2-adrenergic receptor agonist is specified in a group consisting of: a compound of formula (Ia) wherein each of R1, R2 and R3 independently means hydrogen, halogen, (C1-C8)alkyl or alkoxy; each of R4 and R5 independently means hydrogen, (C1-C8)alkyl or alkoxy; each of R6 and R7 independently means hydrogen, nitro, (C1-C8)alkyl or alkoxy; alkoxy is specified in methoxy, ethoxy, n-propoxy, sec-butoxy, tret-butoxy, n-hexyloxy; and a therapeutically effective amount of the non-steroid anti-inflammatory agent diclofenac and a pharmaceutically acceptable carrier, wherein the skin area is subject to or can be injured by an inflammatory skin disease or a symptom related to the above disease. The α2-adrenergic receptor agonist can be presented by, e.g. brimonidine.

EFFECT: ensuring the synergetic effect when using the declared combination which shows the synergetic effect by improving the anti-inflammatory action of diclofenac that leads to the complete relief of any symptoms of the inflammatory disease.

21 cl, 3 ex, 6 tbl, 2 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula (I)CE, wherein "-----" means a bond, V represents CH, and U represents CH or N, or "-----" means a bond, V represents CR6 and U represents CH, or also "-----" means a bond, V represents N and U represents CH, or "-----" is absent, V represents CH, and U represents CH2, NH or NR9; R0 represents H, or provided "-----" means a bond, can also represent C1-3alkoxygroup; R1 represents H, halogen, cyanogroup, C1-3alkyl or ethinyl; R2 represents H, acetyl or a group of formula -CH2-R3; R3 represents H, C1-3alkyl or C1-3hydroxyalkyl; R4 represents H, or provided n is other than 0, and R5 means H, can also represent OH; R5 represents H, C1-3alkyl, C1-3hydroxyalkyl, C1-3aminoalkyl, C1-3alkoxyC1-3alkyl, carboxyl group or C1-3alkoxycarbonyl; R6 represents C1-3hydroxyalkyl, carboxyl group, C1-3alkoxycarbonyl or a group -(CH2)q-NR7R8, wherein q is 1, 2 or 3 and each of R7 and R8 independently represents H or C1-3alkyl, or R7 and R8 together with a nitrogen atom to which they are attached, form a pyrrolodinyl or piperidinyl ring; R9 represents C1-3alkyl, 2-hydroxyethyl, 2-hydroxypropyl or 3-hydroxypropyl; A represents -(CH2)p-, -CH2CH2CH(OH)- or -COCH2CH(OH)-; G represents a phenyl group which is mono- or disubstituted in m- and/or n-position(s)by substitutes independently specified C1-4alkyl, C1-3alkoxygroup and halogen, or G means a group of one of formulas below G1 and G2, wherein Q means O or S, and X means CH or N; and each Y1, Y2 and Y3 represents CH, or one of Y1 and Y3 represents N, and the other one represents CH; and n is equal to 0, provided A represents -CH2CH2CH(OH)- or -COCH2CH(OH)-, and n is equal to 0, 1 or 2, provided A represents (CH2)p, wherein p is equal to 1, 2, 3 or 4, provided a sum of n and p is then equal to 2, 3 or 4; or a pharmaceutically acceptable salt of this compound.

EFFECT: compound of formula (I)CE or its pharmaceutically acceptable salt are applicable as a therapeutic agent for preventing or treating a bacterial infection.

29 cl, 2 tbl, 202 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutically acceptable (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester salts specified in a group consisting of phosphate salt, hydrochloride salt, sulphate salt, mesylate salt, maleate salt or malate salt. Also, the invention refers to a method for preparing the above salts, using them and a pharmaceutical composition on the basis of the above salts.

EFFECT: there are prepared new pharmaceutically acceptable (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid methyl ester salts effective in treating diabetes.

5 cl, 3 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new substituted pyrazino-quinolines of formula: , wherein the values R1, R2, R3, R4, R5, R5a, R6, R7, R8, R9, R10, R11, R12, R13, R14, X and Y are presented in clause one of the patent claim, and to their pharmaceutically acceptable salts.

EFFECT: compounds can be used for treating cancer.

14 cl, 24 dwg, 2 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: treating a wound surface with dioxidine is followed by an infrared laser light with a permanent magnetic field not earlier than 5 days after the operation. Magnetic induction intensity is within the range of 20-50 mT; a laser pulse repetition frequency is within the range of 80 Hz, and a power is 0.25-0.5 W. The whole postoperative area is subject to the daily distant labile exposure to a defocused beam at 0.5 cm for 30-60 seconds. That is followed by applying tissues with hypertonic solution 3 to 5 times a day; the therapeutic course is 10-15 procedures.

EFFECT: method enables providing higher effectiveness and reducing a length of treatment ensured by the integrated exposure to the antibacterial agents and magnetic laserophoresis in the presented regimen, preventing developing postoperative complications.

2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to antibacterial compounds of formula

,

where R1 is an alkoxy group; R2 is H or F; each of R3, R4, R5 and R6 is independently H or D; V is CH and W is CH or N, or V is N and W is CH; Y is CH or N; Z is O, S or CH2 and A is CH2, CH2CH2 or CD2CD2; or a salt of said compound. The invention also describes a antibacterial pharmaceutical composition which contains the compound of formula (I) as a basic component, and use of the compound of formula (I).

EFFECT: obtaining novel compounds possessing useful biological properties.

25 cl, 2 tbl, 24 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to 1-(4-ethylphenyl)-2-[3-(4-ethylphenyl)-2-(1H)-quinoxalinylidene]-1-ethanol of formula (1): .

EFFECT: what is produced is a high-yield new compound possessing a marked analgesic activity which can find application in medicine.

3 ex, 1 tbl

FIELD: organic synthesis.

SUBSTANCE: invention provides compounds of general formula I:

, where R1 represents -CO-Ra, -SO2-Rb, or aryl optionally substituted by lower alkoxy, wherein Ra represents cycloalkyl, cycloalkyl(lower)alkyl, cycloalkyloxy, aryl, aryloxy, aryl(lower)alkyl, aryl(lower)alkoxy, aryloxy(lower)alkyl, aryl-S-(lower)alkyl, aryl(lower)alkenyl, provided that aryl group can be optionally substituted by halogen, lower alkyl, hydroxy, nitro, cyano, lower alkoxy, phenyl, CF3, cyano(lower)alkyl, lower alkyl-C(O)NH, lower alkyl-CO, and lower alkyl-S; heteroaryl, heteroaryl(lower)alkyl, or heteroaryl(lower)alkoxy, provided that heteroaryl group is 5- or 6-membered ring or bicyclic aromatic group constituted by two 5- or 6-membered rings including 1-3 heteroatoms selected from oxygen, nitrogen, and sulfur and that heteroaryl group can be optionally substituted by lower alkoxy; Rb represents aryl, aryl(lower)alkyl, or heteroaryl, aryl group optionally substituted by halogen, cyano, or lower alkyl-C(O)NH; R2 and R3 represent hydrogen atoms; R4 representshydrogen or lower alkyl; R5 represents hydrogen, lower alkyl, cycloalkyl, benzodioxyl, or aryl optionally substituted by lower alkyl, halogen, lower alkoxy, hydroxy, or (lower)alkyl-C(O)O; n is 1 or 2; and pharmaceutically acceptable salts thereof and/or pharmaceutically acceptable esters thereof. Invention also provides a pharmaceutical composition exhibiting inhibitory activity with regard to cysteine proteases of the cathepsin family, which composition comprises compound of formula I, pharmaceutically acceptable recipient, and/or adjuvant.

EFFECT: increased choice of cysteine protease inhibitors.

34 cl, 1 tbl, 13 ex

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