Transdermal therapeutic system

FIELD: medicine.

SUBSTANCE: invention refers to medicine. There are described Transdermal Therapeutic Systems having a silicone adhesive layer, and a method for producing and using them.

EFFECT: transdermal therapeutic systems provide achieving a certain plasma concentration.

23 cl, 3 tbl, 4 dwg, 1 ex

 

The present invention relates to Transdermal Therapeutic Systems containing protective layer, the reservoir layer and the adhesive layer, to Transdermal Therapeutic Systems, with a specific release profile, their manufacture and use.

Transdermal Therapeutic System (TTS) and make them widely known in this field. In EP 1047409 described TTC containing rivastigmine and antioxidant. In GB 2203040 described TTC containing rivastigmine and hydrophilic polymer.

Such TTS possess valuable properties. However, there is a need to create other TTC with improved properties. In particular, there is a need to create a TTS with greater convenience for adherence to treatment regimens, improved adhesion, tolerability and/or safety.

Thus, the aim of the present invention is to provide TTC with greater convenience for adherence to treatment regimens, improved adhesion, tolerability and/or safety.

Another objective of the present invention is the creation of TTS, which contains a relatively large amount of active substance and has an adhesive strength that is sufficient to ensure reliable attachment during the entire period of use.

Following a the Yu of the present invention is the creation of TTS, which contains a relatively large amount of active substance, but it does not have an excessively large size.

Another objective of the present invention is the creation of TTS, which has improved adhesive properties, but retains without change the release profile of the active substance.

The next objective of the present invention is to develop a method of treatment and composition(s) controlled release, which can significantly increase the effectiveness and tolerability of rivastigmine.

The next objective of the present invention is to develop a method of treatment and composition(s) controlled release, which can significantly reduce the time and resources required for the introduction of rivastigmine to ensure favorable therapeutic actions.

The next objective of the present invention is to develop a method of treatment and composition(s) controlled release, which can significantly increase the degree of convenience for the compliance of patient treatment with the use of rivastigmine.

The next objective of the present invention is to develop a method of treatment and composition(s) controlled release, providing less evidence of variation in concentrations of rivastigmine in PL is the ZMA, needed to achieve therapeutic favorable action is not accompanied by unacceptable side effects.

These goals are achieved through TTC described in claim 1 and dependent claims.

In the drawings shown:

figure 1 is a bar chart illustrating the difference between the adhesive force of the TTC, with additional silicone adhesive layer (TTC number 2), and the adhesive force TTS, no additional silicone adhesive layer (IDT No. 1);

figure 2 is a graph illustrating the difference between the speed of penetration of rivastigmine through the entire thickness of the human skin with the introduction using TTS, with additional silicone adhesive layer (TTC number 2), and TTS, no additional silicone adhesive layer (IDT No. 1);

figure 3 is a graph illustrating the difference between the speed of penetration of rivastigmine through EVA-membrane with the introduction using TTS, with additional silicone adhesive layer (TTC number 2), and TTS, no additional silicone adhesive layer (IDT No. 1);

figure 4 is a graph illustrating the pharmacokinetic (PK) profiles in plasma after administration by capsule (upper panel) and using TTC number 2 (bottom panel).

The experiments conducted with the use of active substances which are used for treatment b is Lesni Alzheimer's disease, unexpectedly demonstrated that having a weak adhesive capacity of the reservoir matrix can be applied film silicone adhesive, thereby significantly increasing the adhesive properties of the drug without deterioration of thermodynamic properties of TTS, i.e. not reducing the release of active substance from the matrix and its penetration through the skin.

The results of experiments on transdermal introduction of active substances used for the treatment of Alzheimer's spent creating the present invention, it is possible, of course, transferred to other groups of active substances. Thus, in General, it can be argued that for many active substances increasing the proportion of active substance in the adhesive polymer matrix TTC leads to a significant reduction of the adhesive properties of the TTS, if the active ingredients are in the solid state at room temperature. Generally, if the active substances are in liquid state at room temperature, to achieve the ability to machining of polymers is necessary to add large amounts of so-called "thickening polymers (e.g. cellulose or polyacrylate derivatives), which also leads to reduced adhesive properties.

In the present invention proposed TTC, consisting of protective the layer, reservoir layer, which contains at least one active substance and the polymer adhesive layer consisting of a silicone polymer and a substance for improving adhesiveness,

TTC proposed in the invention, has superior adhesive properties. In addition, what is totally unexpected, the thus created TTC has almost the same release profile as standard TTC.

The present invention relates also to method can significantly improve the effectiveness and tolerability of rivastigmine, which is that used TTC ranging from 2 to 50 cm2where the composition provides a mean maximum concentration of the active substance in plasma, comprising from 1 to 30 ng/ml on average approximately 2-16 h after application, and the value of AUC24 hoursapproximately 25 to 450 ng·h/ml after repeated "QD" (i.e. daily) introduction.

Unexpectedly, it was found that TTC proposed in the invention has greater portability, primarily related to the gastrointestinal tract side effects, such as nausea and vomiting, compared with equivalent exposure levels (UC24 hours) capsules Exelon®.

Unless otherwise stated, used in the present description, the terms have the following values.

is he notion of "transdermal therapeutic system" refers to any device allowing the release of the pharmaceutical active substance through the skin. It refers, in particular, to other devices, such as patches.

The term "protective layer" means the layer is not in contact with the skin. This layer preferably is impermeable to the active substance. You can apply any suitable material or combination of materials. For example, it is possible to use polyethylene terephthalate (PET), polyethylene, polypropylene, polyurethane, etc.

The term "reservoir layer" denotes a layer containing one or more active substances associated with one or more polymers. In a preferred variant of the invention, the reservoir layer contains the active substance in the form of a polymeric matrix.

The term "adhesive layer" means the layer facing the skin. This layer consists of silicone (silicone) polymer substances to improve adhesiveness.

The concept of "detachable protective layer" means a layer that is removed from the adhesive before application to the skin. This layer preferably is impermeable to the active substance. You can apply any suitable material or combination of materials. For example, you can use siliconized PET, siliconized polypropylene, siliconised the cell polyethylene, PET coated with fluorocarbon resin, polypropylene, coated with fluorocarbon resin, polyethylene, coated with fluorocarbon resin, etc.

The term "active substance" refers to any active substance suitable for transdermal administration. To the active substances are water-soluble and water-insoluble pharmaceutical active substances which can be an inorganic or organic substance. Preferred are organic substances. The active substances are substances which are used in accordance with their purpose as analgesics, antipyretics, Antirheumatic means, sedatives, hypnotics, anti-epileptics, depressants and stimulants, anaesthetics, adjunct analgesics, antihistaminics funds, antihypertensive agents, anticoagulants, antithrombotic funds, psychopharmacological agents, Psycholeptics funds, chemotherapeutic agents, such as antibiotics, sulfonamides, anti-tuberculosis drugs (tuberculostatic funds) or chemotherapeutic agents against tropical infections, diuretics, antispasmodics, cardiovascular drugs, for example sympathomimetic funds,hypotensive means, pacemakers, such as cardiac glycosides and digitality, parenteral therapeutic agents to normalize sugar levels, analepticheskih means acting on the Central nervous system, geriatric funds tonalities funds (striated muscle), antiparkinsonian funds, cytostatic agents, immunosuppressants, tonics and vitamins, as indicated in B. Helwig has created, Moderne Arzneimittel, 1980.

Preferred active substances are selected from the group including agonists, α-adrenergic receptors, agonists of β-adrenergic receptors blockers, α-adrenergic receptors anesthetic analgesic funds panetteria analgesic tools, androgens, anesthetics, anti-allergic medicines, anti-androgens, anti-money, anti-arrhythmic means, penicillins, antidiabetic agents, antihistamines, protivotecheniya tools, hydrated ergotalkaloids, CA++antagonists, serotonin antagonists, platelet aggregation inhibitors, antidepressants, bronchodilators, estrogens, gestagens, vasodilator, hormones, drugs against dementia (including cholinesterase inhibitors).

The preferred antibiotics are penicillin, tetracycline, chlortetracycline is, bacitracin, nystatin, streptomycin, neomycin, polymycin, gramicidin, oxytetracycline, chloramphenicol, erythromycin, rifampicin, Cefazolin, cefoxitin, cefsulodin, cefotiam and mefoksin.

Preferred chemotherapeutic agents are sulfamethazine, sulfamerazine, sulfamethizole and sulfoxides. The preferred sedative and sleeping facilities are chloral hydrate, pentobarbital, phenobarbital, secobarbital, codeine and carbama. The preferred cardiac glycosides and digitalonly are digitoxin and digoxin. For your preferred sympathomimetics is epinephrine.

When carrying out the invention in practice, as an active substance in a suitable water-soluble form or water-insoluble form may be used, in particular, antipyretic agents, analgesic tools and Antirheumatic agents, such as propifenazona, aminophenazone, aspirin (ASA), phenazone, methylnitrate, millencolin, sulfinate, phenacetin, pentazocine, lactoferin, paracetamol, quinine, floranova acid, mefenamovaya acid, telenova acid, meclofenamic acid, niflumova acid, clonixin or clonixin, flunixin, ibuprofen, suprofen, Ketoprofen, fenoprofen, pirprofen, diclofenac, ibufenac, practicesa acid, naproxen, cicloprofen, t is Latin, cloirec, tiaprofenic acid, oxaprozin, fenclova acid, fentiazac, clidanac, fenglong, fenoprofen, flurbiprofen, carprofen, sulindac, cinmetacin, fenbufen, etodolac, butibufen.

Preferred psychopharmacological agents are neuroleptics, antidepressants, timolepticheskoe funds timerelease drugs and tranquilizers, such as thioridazine, imipramine, desimipramine, clomipramine, ketimipramine, opipramol, amitriptyline, nortriptyline, reserpine, Aromasin, chlorpromazine, fluororesin, melipramin, trimeprazine, dietzen, promethazine, aminopropanol, maasin, pipamazine, maprotiline and memantine.

The preferred antihypertensive agents are oxprenolol and metoprolol.

Preferred active substances are selected from the group comprising drugs against dementia, such as rivastigmine, donepezil, galantamine, saligenin, memantine and pharmaceutically acceptable salts of these active substances.

The preferred cholinesterase inhibitors are taken, rivastigmine, donezepil, galantamine, physostigmine, huperzine and their pharmacologically acceptable salts.

Preferred is a combination of rivastigmine and memantine as active substances.

The most preferred active ingredients of ybiraut from the group including rivastigmine and acid tartrate rivastigmine. Rivastigmine (Exelon®) used in the treatment of patients suffering from dementia type (also known as Alzheimer's disease) and mild to moderate severity, dementia associated with Parkinson's disease and symptoms of traumatic brain damage.

The term "polymer" when used in relation to reservoir layer containing the active substance, denotes a polymer selected from the group comprising polydimethylsiloxane, polyacrylates, polyisobutene, polybutene and block copolymers of styrene-isoprene and mixtures thereof, respectively, are combined with the resin.

Preferred polymers intended for use in reservoir layer, selected from the group consisting of polyacrylates, such as Durotak 2353 from the company National Starch.

The term "silicone polymer" refers to polymers based polymethylsiloxane, for example aminomethyl Bio-PSA Q7-4302 from Dow Corning.

The notion of "substance to increase stickiness" refers to a substance that increases the adhesiveness/stickiness transdermal composition. Preferred substances for improving the adhesiveness is chosen from the group comprising silicone oils, esters of glycerin and hydrogenated resin acids, hydroabietyl alcohol, esters smola what's acids, hydrogenated methyl ester extraction of rosin, an ester of partially hydrogenated extraction of rosin, esters of rosin, etc. and combinations thereof. The person skilled in the art know that TTC consist of several layers with specific characteristics. These layers may vary from the point of view of a particular composition and thickness of the individual layers.

In a preferred embodiment of the present invention applied active substances have low solubility limit in silicon adhesive. The solubility limit of the active ingredient in the silicone adhesive is, for example, less than 15 wt.%, preferably less than 10 wt.% and most preferably from 2 to 8 wt.%.

Silicone adhesive layer preferably reduces the penetration of the active substance from the reservoir layer through the skin, not more than 40%, more preferably not more than 20% and even more preferably not more than 10%.

The weight of the silicone adhesive layer per unit area is, for example, from 5 to 60 g/m2preferably from 10 to 30 g/m2.

The composition proposed in the invention can be used to integrate a wide variety of active substances. Suitable active substances are substances that are listed is use.

In a preferred variant of the invention, the reservoir layer, in addition, contain excipients, such as fillers, antioxidants, dyes, substances that enhance penetration through the skin, and/or preservatives. Such excipients are known to the expert and their description can be found in standard handbooks, such as Fiedler, Lexicon der Hilfstoffe, 4th ed., publishing house ECV Aulendorf, 1996 and Handbook of Pharmaceutical Excipients, edited by Wade and Weller, 1994, the contents of which are incorporated into this description by reference.

In the most preferred embodiment of the invention the reservoir layer contains an antioxidant such as α-tocopherol, ascorbyl palmitate or bottled hydroxytoluene (OSH).

In a preferred variant of the invention, the reservoir layer contains a substance that enhance penetration through the skin, such as transcutol, glycerin, complex glycerol esters, fatty acids, salts of fatty acids, azone, diethyltoluamide, propylene glycol, esters of propylene glycol, butanediol, complex isopropyl esters, urea, etc.

In a preferred embodiment of the invention the ratio of the thickness of the reservoir layer to the thickness of the adhesive layer is from 5:1 to 1:2; preferably from 2:1 to 1:1.

In a preferred embodiment, izaberete the Oia TTC has adhesive force > 5 N/10 cm2preferably >10 N/10 cm2. In a preferred embodiment of the invention TTC has adhesive force <100 N/10 cm2preferably <50 N/10 cm2. Adhesive strength determined according to a standard method, for example, as described in the examples.

In a preferred embodiment of the invention TTC has a size of from 2 to 50 cm2most preferably from 5 to 20 cm2.

In a preferred embodiment of the invention TTC provides average and maximum concentrations of rivastigmine in plasma, reaching 1-30 ng/ml on average through 2-16 h after application, the value of the AUC24 hoursranges from 25 to 450 ng·h/ml, most preferably TTC provides average and maximum concentrations of rivastigmine in plasma, reaching 2.5 to 20 ng/ml on average after 4-12 h after application, the value of the AUC24 hoursranges from 45 to 350 ng·h/ml

In another embodiment of the invention, not only the polymer matrix, but also silicone adhesive layer contains a valid(s) substance(s).

Another object of the invention is TTS, which contains as active substance a cholinesterase inhibitor in free form or in the form of a pharmaceutically acceptable salt intended for use for the prevention, treatment sludge is slowing down the development of dementia.

The next object of the invention is a method of prevention, treatment or delay the development of dementia associated with Parkinson's disease in an individual in need of such treatment, which is that the individual is treated in a therapeutically effective amount of TTS, which contains as active substance a cholinesterase inhibitor in free form or in the form of pharmaceutically acceptable salts.

Another object of the invention is a method of preventing, treating, or slowing the development of Alzheimer's disease in an individual in need of such treatment, which is that the individual is treated in a therapeutically effective amount of TTS, which contains as active substance a cholinesterase inhibitor in free form or in the form of pharmaceutically acceptable salts.

Manufacturer IDT proposed in the invention can be carried out by any method known to a person skilled in the field.

The next object of the invention is the preferred method of manufacture of TTC. This method lies in the fact that

a) prepare the active substance in the adhesive mortar,

b) make the layer comprising the active substance in the adhesive mortar,

C) dried active substance in the adhesive solution,/p>

g) prepare silicone adhesive mortar,

d) make a layer of silicone adhesive mortar,

e) place a layer of silicone adhesive on the drug in the adhesive layer,

W) are punched and Packed.

Another object of the invention is TTS, which contains as active substance rivastigmine in free base form or in the form of pharmaceutically acceptable salts and provides certain concentration of active substance in the plasma.

There is little published data about biopharmacological properties of rivastigmine in the human body. It is rapidly and completely absorbed. In the claimed invention, it was found that it is metabolized primarily as a result of hydrolysis by esterases, such as acetyl - and butyrylcholinesterase, and its half-life in plasma is 1 hour It is exposed predestina and systemic metabolism. While the invention has been installed that can be created containing rivastigmine TTC, which have improved properties, for example, better portability.

Thus, in the invention proposed TTC, containing as active substance rivastigmine in free base form or in the form of a pharmaceutically acceptable salt, which provides average maximum conc is Tracey of rivastigmine plasma, reaching approximately 1-30 ng/ml on average through 2-16 h after application.

In addition, in the invention proposed TTC, containing as active substance rivastigmine in free base form or in the form of a pharmaceutically acceptable salt, which provides a mean maximum concentration of drug substance in plasma, comprising from 1 to 30 ng/ml on average approximately 2-16 h after application, and the value of AUC24 hoursapproximately 25 to 450 ng·h/ml after repeated "QD" (i.e. daily) introduction.

The person skilled in the art know how to make the TTC to satisfy the above profiles of the active substance in the plasma. Specialist in this field should be obvious that such profiles in the plasma can be obtained, for example, by varying:

- the first and/or second components, for example, the nature and amount of excipients and/or current(s) of the substances(a)

- type adhesive layer,

- the size of the patch.

TTC can be produced, taking into account the following aspects:

- the period of time prior to the release of the active substance (the lag time or delay time),

the rate of release of the active substance (fast or slow release),

the duration of release of the active substance (long sludge is short),

- reduced first pass metabolism,

- improving facilities for patients ' adherence to treatment,

- decrease the frequency of application.

Such aspects can be studied using standard experiments to assess the solubility in vitro, for example, in water or, if necessary, in a common water body, such as in artificial gastric juice.

There is little published data about strong compositions with controlled time release to unleash in a predefined time single or repeated doses of active substances. There is a need to create such compositions, acceptable from a commercial point of view.

As a result of extensive studies conducted in the claimed invention, it was found that you can create TTS, which is capable of releasing at a certain time, for example with a certain time lag or time delay, the pharmaceutical active ingredient or mixture of active substances, for example, almost regardless of the concentration and type of ions present in the gastrointestinal environment, for example, hydrogen ions and hydroxyl ions, i.e. regardless of the value of pH, phosphate ions, and regardless of the enzymes present in the environment total water body.

Under this the image the structure rivastigmine can be used in free base form or in the form of its pharmaceutically acceptable salts. Preferably used free base.

The exact magnitude of the doses of the active substance and TTC, intended for use, depend on many factors, such as the condition to be treated, the desired duration of treatment, and the speed of release of the active substance.

For example, the required amount of the active substance and its rate of release can be determined using known methods in vitro or in vivo by assessing the time within which a specific concentration of the active substance in the blood plasma remains acceptable for therapeutic action.

For example, rivastigmine can be applied dose in the range from 1 to 12 mg of active ingredient per day for a mammal weighing 70 or 75 kg, such as a person, and on standard models with animals.

TTC proposed invention allows, for example, to prepare a pharmaceutical form that can be applied once a day for patients who need to take more than one dose of active ingredient per day, for example, at specific points in time, to simplify the treatment. Using such compositions can be improved tolerability of rivastigmine, which allows you to use a higher starting dose and to reduce the number of stages of the titration of the doses.

Increasing the military tolerability of rivastigmine, provide compositions that can be demonstrated in standard animal experiments and in clinical trials.

Below the invention is illustrated in the examples, not limiting its scope.

Example 1

I. Receiving TTS

Below, as an example, experiments were performed with the use of cholinesterase inhibitor of rivastigmine, in free base form. For experiments produced two described below TTS:

TTC # 1: you Made the pieces of the substrate with a mass per unit area of 60 g/m2having the following structure:

Rivastigmine (free base)30.0 wt.%
Durotak® 387-2353 (polyacrylate adhesive)to 49.9 wt.%
Plastoid® (acrylate copolymer)20.0 wt.%
vitamin E0.1 wt.%

TTC # 2: the Produced pieces of the substrate in the form of a double layer (bilayer), where one layer of the bilayer corresponded to TTC number 1. On the specified layer was applied silicone adhesive layer with a mass per unit area of 30 g/m2having the following structure:

Bio-PSA® Q7-4302 (with Likhovy adhesive) the 98.9 wt.%
silicone oil1.0 wt.%
vitamin E0.1 wt.%

The solubility limit of rivastigmine in free base form in the silicone adhesive is about 5 wt.%.

II. Determination of adhesive strength

The adhesive strength of both TTC were determined using methods known to experts in this field, taking into consideration the following factors:

- the size of the pieces of substrate: 10 cm2,

test plate: steel plate,

- the angle of exfoliation: 90°,

- the rate of exfoliation: 300 mm/min

The adhesive strength obtained for both TTC presented in figure 1. The diagram presented in figure 1, demonstrates that the application of acrylate adhesive matrix coating representing silicone adhesive layer, significantly increased adhesive strength.

Rivastigmine in free base form is in a liquid state at room temperature. Therefore, for inclusion of the active substance in the amount of 30 wt.% you need to add "thickening polymer" (Plastoid®). The result obtained substrate having a low adhesive strength. When using the optional silicone adhesive layer, the adhesive is th power is about five times greater than the adhesive force of TTC without additional adhesive layer, with which it was made the comparison.

III. The penetrating ability

In order to determine whether the application of additional silicone adhesive layer on the release of the active substance, carried out experiments to study the penetration of rivastigmine through the entire thickness of the human skin and EVA membrane using both TTC. For these experiments for the study of penetration used the following criteria.

Pieces of human skin full thickness and EVA-membranes, respectively, were made in the modified diffusion cell Franz. The surface area through which happened diffusion was rate of 1.51 cm2. As acceptor medium used phosphate buffer (pH 5.5)containing 0.1% of sodium azide. The volume of the acceptor medium was 9 ml Temperature at which carried out the experience drove through the water bath up to 32°C, which corresponds to the surface temperature of human skin in vivo.

The acceptor medium was completely replaced with fresh acceptor solution through 8, 24, 32, 48, 56 and 72 h in order to ensure strict observance of the flow conditions during the whole period of the experiment.

The content of rivastigmine in the acceptor medium was determined using GHUR.

The results of the experiments on the study of the penetration are presented in graph form in figure 2 and 3.

The result is evidence of the fact, two TTC was not revealed virtually no difference between the speed of penetration of rivastigmine in free base form through human skin (figure 2). Small differences, apparently, due to the use of biological material, which is the skin, and can be explained by the presence of local variations, for example, the type of micro-damage or hair follicles.

To eliminate variations due to the use of biological material, experiments to study the penetration was repeated using artificial membrane (EVA-membrane). The results presented in figure 3, confirmed the data obtained using human skin with full thickness, namely that both TTC did not differ in their ability to provide for the penetration.

It has been unexpectedly found that the use of additional silicone adhesive layer did not influence the penetration of the active substance through the skin.

Thus, according to the present invention can be produced TTC, which have significantly higher adhesive force, while maintaining their original size.

IV. The pharmacokinetic characteristics of

Conducted outdoor consisting of four periods of experience in parallel groups with the use of proportionally increasing doses of assessment TT is No. 2 with an area of 5, 10, 15 and 20 cm2and capsules Exelon®1.5, 3, 4.5 and 6 mg (bid) in patients with a stationary state of Alzheimer's disease from mild to moderate.

Patients diagnosed with Alzheimer's disease from mild to moderate, were distributed randomly into groups that were treated either with TTC number 2, or by using capsules. Inclusion criteria were as follows: patients male or female (not with reproductive potential), aged 50-85 years that meet the criteria (DSM-IV) dementia in medical literature type. Patients had to be diagnosed with probable AD according to the criteria of NINCDS - ADRDA with MMSE-score of 10-26 (including both limits), and should not present any other medical conditions that could influence the results of the experiment.

Based on the experience of previous clinical studies, this study used the 14-day stage of the titration.

In this analysis, each of the four periods has completed the following number of patients and the resulting data used to evaluate the pharmacokinetic characteristics:

CapsuleTTC number 2
19 patients, the dose of 1.5 mg bid 18 patients, the dose of 5 cm2
18 patients, the dose of 3.0 mg bid18 patients, the dose of 10 cm2
13 patients, the dose of 4.5 mg bid16 patients, the dose of 15 cm2
12 patients, the dose of 6.0 mg bid11 patients, the dose of 20 cm2

Pharmacokinetic characteristics of rivastigmine studied for each type of processing on the last day of each period titration except higher doses when they were studied on the third day titration (in order not to miss sampling the plasma in the case of premature exclusion from the experience due to poor tolerability). Plasma samples were analyzed in respect to the content of rivastigmine using LC-MS/MS with a lower limit of quantification (LLOQ), amounting to 0.2 ng/ml Standard decompartmentalise pharmacokinetic parameters were calculated on the basis of individual profiles based plasma concentration time using WinNonlin Pro.

Pharmacokinetic parameters of rivastigmine are summarized in table 1 (treatment using capsules) and table 2 (treatment using TTC number 2). According to (profiles) average (± SCO) plasma concentration from time presents nafig.

When using TTC # 2 concentration of rivastigmine was on the plateau of the median value of tmax; average of 8.0 hours for all sizes TTC. Output increased disproportionately with increasing dose, as shown in table 3, but to a lesser extent than when using capsules, primarily regarding AUC24 hours.

Evidence of variability, which was assessed using coefficients of variation (CV) for the parameters of the exit (release) of rivastigmine (Cmaxand AUC24 hours), as a rule, was lower when using the patch (size CV was 33-48%)than with oral administration (CV values were 39-68%).

V. Pharmacological properties

Using standard animal experiments and clinical experiences 5 found that TTC number 2 has a higher pharmacological properties compared with the composition in the form of capsules.

Table 1
The results of the descriptive statistical analysis of pharmacokinetic parameters of rivastigmine after the introduction capsules
ENA713Morning doseEvening dose Daily dose
Cmax(ng/ml)tmax(h)AUC12h, (ng·h/ml)AUC12last(ng·h/ml)t1/2(h)Cmax(ng/ml)tmax(h)AUC12h(ng·h/ml)AUC12last(ng·h/ml)t1/2(h)AUC24 hours(ng·h/ml)
1.5 mg bid (3 mg / day)
mean ± SKO3,71±2,547,01±4,28of 6.68±4,271,27±0,252,37±1,475,27±3,314,94±3,271,37±0,4012,3±7,41
CV%68616420626368 2960
medianwas 2.761,05,445,11of 1.341,611,04,674,471,43being 9.61
min1,170,51,991,840,750,9010,51,64the 1.440,553,63
max10,83,018,718,41,695,864,013,112.82,00of 31.8
T19191919 18191919191819
1.5 mg bid (3 mg / day)
mean ± SKO9,82±4,9929,3±16,429,0±16,51,55±0,27EUR 7.57±3,9023,4±13,123,2±13,11,74±0,3452,7±29,2
CV%515657175256572055
median10,51.028,127,71,626,591,022,1 21,71,7251,8
min2,680,5by 8.228,010,992,480,56,696,321,18the 17.3
max21,33,065,065,01,9316,54,050,350,32,31114
N1818181817181818181818
1.5 mg bid (3 mg / day)
mean ± SKO 15,7±6,6850,6±25,050,4±25,11,73±0,2610,6±4,1239,8±20,439,7±20,52,05±0,46to 90.4±45,1
CV%434950153951522250
medianthe 15.61,046,546,51,6810,91,538,238,22,0284,7
min5,440,524,223,81,304,55 0,7515,014,71,5241,2
max25,52,01191192,2719,86,093,693,63,14213
N1313131313131313131313
1.5 mg bid (3 mg / day)
mean ± SKO30,2±14,8to 82.1±31,1to 82.1±35,21,75±0,2419,3±9,2968,3±28,270,0±28,61,93 the 0,27 150±58,8
CV%493838144841411439
median26,70,8872,171,11,7018,81,0of 60.562,61,96129
min12,50,5035,735,71,438,650,7530,730,71,4966,4
max66,02,0131131 2,2436,93,01141142,43242
N1212121212121212121112

Table 2
The results of descriptive statistical analysis pharmacokinetic× parameters rivastigmine after applying TTS No. 2
ENA713Cmax(ng/ml)tmax(h)AUC24 hours(ng·h/ml)AUC1ast(ng·h/ml)t1/2(h)
5 cm2
(loaded
the dose of 9 mg)
mean ± SKO2,66±1,1545,6±16,645±16,6the concentration is
CV%433636the concentration is
median2,668,048,348,3the concentration is
min1,190,519,719,7the concentration is
max4,63to 12.074,974,9the concentration is
N18 181818the concentration is
10 cm2
(loaded
dose of 18 mg)
mean ± SKOEUR 7.57±2,74123±41,0123±41,0the concentration is
CV%363333the concentration is
medianof 7.758,0121121the concentration is
minwas 2.763,0 58,558,5the concentration is
maxto 12.016,0199199the concentration is
N18181818the concentration is
15 cm2
(loaded
dose of 27 mg)
mean ± SKO13,8±6,58266±85,5226±85,5the concentration is
CV%4838 38the concentration is
medianthe 15.68,0243243the concentration is
min4,323,093,693,6the concentration is
max25,716,0346346the concentration is
N16161616the concentration is
20 cm2
(loaded
dose of 36 mg)mean ± SKO19,0±8,04339±138397±1543,40±0,67
CV%42413920
median17,18,03233683,24
minat 7.550,01401802,60
max33,7to 12.0529598to 4.62
N1111111111
the concentration - not determined

Table 3
The degree of increase of the output of rivastigmine with increasing dose
RivastigminecapsuleTTS No. 2
doseWithmaxAUC24 hoursWithmaxAUC24 hours
×2×2,6×4,3×2,8×2,7
×3×3,8×7,3×5,2×5,0
×4×7,3×12,2×7,1×7,4

1. Transdermal Therapeutic System (TTS)containing
a) a protective layer,
b) a reservoir layer containing rivastigmine in free base form or in the form of pharmaceutically acceptable salts as pharmaceutical active substance, and one or more polymers,
C) an adhesive layer containing a silicone polymer and an agent for improving adhesiveness, where the substance to improve the adhesiveness of silicone is m the words,
where the active substance has a maximum concentration in plasma is approximately from 1 to 30 ng/ml after about 2-16 hours

2. TTS according to claim 1, which contains rivastigmine in free base form or in the form of pharmaceutically acceptable salts, and which provides the maximum concentration in plasma, reaching about 2.5-20 ng/ml after approximately 2-16 h after application.

3. TTS according to claim 1, which contains as active substance rivastigmine in free base form or in the form of pharmaceutically acceptable salts, and which provides the value of the AUC24 hoursapproximately 25 to 450 ng·h/ml after repeated daily administration.

4. TTS according to claim 3, which contains as active substance rivastigmine in free base form or in the form of pharmaceutically acceptable salts, and which provides the value of the AUC24 hoursapproximately 45 to 340 ng·h/ml after repeated daily administration.

5. TTS according to claim 1, where the TTC has an adhesive force >5 N/10 cm2in particular >10 N/10 cm2in particular <50 N/10 cm2in particular <100 N/10 cm2.

6. TTS according to claim 1, where TTC is the path.

7. TTS according to claim 6, where the size of the track has a size in the range 2-50 cm2in particular 5-20 cm2.

8. TTS according to claim 7, where the size of the track has a size of 5 cm2with a loading dose is a key rivastigmine 9 mg.

9. TTC by according to claim 7, where the size of the track has a size of 10 cm2with a loading dose of rivastigmine 18 mg

10. TTC by according to claim 7, where the size of the track has a size of 15 cm2with a loading dose of rivastigmine 27 mg.

11. TTS according to claim 7, where the size of the track has a size of 20 cm2with a loading dose of rivastigmine 36 mg.

12. TTS according to claim 1, where the protective layer is impermeable to the active substance.

13. TTS according to claim 1, further comprising a detachable protective layer.

14. TTS according to claim 1, characterized in that the active substance has a solubility limit in silicon adhesive constituting less than 15 wt.%, preferably less than 10 wt.% and most preferably from 2 to 8 wt.%.

15. TTC for 14, characterized in that the silicone adhesive layer can reduce the penetration of the active substance from the reservoir layer through the skin, not more than 40%.

16. TTC by § 15, characterized in that the weight of the silicone adhesive layer per unit area is from 5 to 60 g/m2.

17. TTS according to claim 1, characterized in that the active substance is selected from the group comprising rivastigmine and sour rivastigmine tartrate.

18. TTS according to claim 1, characterized in that the reservoir layer contains a polymer selected from the group comprising polydimethylsiloxane, acrylates, methacrylates, polyisobutene, polybutene and block copolymers of styrene-isoprene and MESI, respectively, are combined with the resin.

19. Transdermal Therapeutic System (TTS)containing
a) a protective layer,
b) a reservoir layer containing rivastigmine in free base form, in the form of a pharmaceutically acceptable salt or memantine as a pharmaceutical active substance, and one or more polymers,
C) an adhesive layer containing a silicone polymer and an agent for improving adhesiveness, where the substance to increase the stickiness selected from the group comprising silicone oil, glycerin esters of hydrogenated resin acids, hydroabietyl alcohol, esters of resin acids, hydrogenated methyl ester extraction of rosin, an ester of partially hydrogenated extraction of rosin, esters of rosin, and combinations thereof, where the active substance has a maximum concentration in plasma is approximately from 1 to 30 ng/ml after about 2-16 hours

20. TTS according to claim 19, characterized in that the active substance contained in the silicone adhesive layer.

21. TTS according to claim 19, containing as active substance rivastigmine and memantine.

22. The application of the TTS according to any one of claims 1 to 21 for the preparation of medicines for the prevention, treatment or delay the development of Alzheimer's disease, dementia, associirovat is Noah with Parkinson's disease, symptoms of traumatic brain damage.

23. The application of the TTS according to any one of claims 1 to 21 for the prevention, treatment or delay the development of Alzheimer's disease, dementia associated with Parkinson's disease, symptoms of traumatic brain damage.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention refers to medicine. What is disclosed is a dosage form containing a base and a self-adhesive layer which contains a medicinal agent and covers at least one of the base sides; wherein the base consists of a polyester film of the thickness of 0.5 to 6.0 mcm, and a polyester non-woven material directly coupled with the film. The base is coated with the self-adhesive layer either directly or through an intermediate layer from the non-woven material.

EFFECT: adhesive preparation have sufficient elasticity for the purpose of tracking of the skin shape, as well as shows low ability to irritate the skin and high stability.

7 cl, 5 tbl, 7 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine. What is described is a film containing as a film-forming agent an alginic acid salt with monovalent cation or mixed alginic acid salts containing at least one alginic acid salt with monovalent cation with 10% aqueous solution of the film-forming agent at temperature 20°C characterised by the viscosity of 100-1000 mPa-sec in accordance with the values measured at shear velocity 20 rpm with using a Brookfield viscometre equipped with a spindle No.2, as well as a method for making such film.

EFFECT: film is applicable for active ingredient delivery in a mammal's body and fast soluble while contacting with a wet surface.

18 cl, 2 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, namely an adhesive preparation for percutaneous introduction of 2-(4-ethyl-1-piperazinyl)-4-(4-fluorophenyl)-5,6,7,8,9,10-hexahydrocyclooctate[b]pyridine (compound A). The preparation contains an adhesive layer formed on one base surface wherein the adhesive layer contains (1) the compound A or its physiologically acceptable salt formed by salt addition, and (2) an acryl adhesive, or (1) the compound A or its physiologically acceptable salt formed by salt addition, (2) the acryl adhesive and (3) a permeability enhancing agent.

EFFECT: preparation inhibits metabolite generation and continuously maintains the blood drug concentration.

19 cl, 7 tbl, 1 dwg, 63 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine. What is described is an adhesive composition which decreases a number of donepezil related compounds formed in the donepezil-containing adhesive composition containing one, two or more types of combinations of the compounds selected from the following groups of the combinations of the compounds from (a) to (j) which are mixed in a layer of a donepezil-containing pressure sensitive glue: (a) isoascorbic acid or its metal salts and 2-mercaptobenzimidazole; (b) isoascorbic acid or its metal salts and 2,6-di-tert-butyl-4-methylphenol; (c) isoascorbic acid or its metal salts and metal salts of hydroxymethane sulphinic acid; (a) isoascorbic acid or its metal salts and rutin; (e) 2-mercaptobenzimidazole and 2,6-di-tert-butyl-4-methylphenol; (f) 2-mercaptobenzimidazole and metal salts of of hydroxymethane sulphinic acid; (g) 2-mercaptobenzimidazole and rutin; (h) 2,6-di-tert-butyl-4-methylphenol and metal salts of hydroxymethane sulphinic acid; (i) 2,6-di-tert-butyl-4-methylphenol and rutin; and (j) metal salts of hydroxymethane sulphinic acid and rutin.

EFFECT: adhesive composition is highly reliable and stable.

12 cl, 2 tbl

Adhesive product // 2441649

FIELD: medicine.

SUBSTANCE: invention describes adhesive product consisting of stretchable base and adhesive layer that is put in thin layer on at least one side of the base, where the stretchable base contains connective layer of fabric subject to goffering process, the adhesive layer contains 10% by weight or more of methyl salicylate from total mass of the layer, moisture permeability of all adhesive product is 1-350 g/m2*24 hours measured at the temperature 40°C and relative humidity 90%, and methyl salicylate has AUC0-24 in plasma in the range from 3.0 to 60.0 ng*h/ml in the values of average ± standard deviation, salicylic acid as the metabolite of methyl salicylate has AUC0-24 in plasma in the range from 5,000 to 13,000 ng*h/ml in the values of average ± standard deviation, when the adhesive product is put on the human skin for 8 hours so that the contacting amount of adhesive layer is 50-300 g/m2 and the area of contact is 280 cm2.

EFFECT: product is capable of stable absorption through the skin.

7 cl, 3 tbl, 3 dwg, 6 ex

FIELD: medicine.

SUBSTANCE: claimed invention relates to medicine, in particular to device for transdermal bisoprolol introduction, which includes base and layer of sensitive to pressure adhesive, which contains bisoprolol, which is layered on one base surface, where maximal value of bisoprolol release in time period immediately from application on skin within 24 hours constitutes 30 mcg/cm2/hour or less; and where velocity of bisoprolol release 24 hours after application on skin constitutes 10 mcg/cm2/hour or less.

EFFECT: device for transdermal introduction reduces skin irritation, especially in case of layering, and can constantly introduce into living organism therapeutically or preventively efficient amount of bioprolol.

5 cl, 3 tbl, 3 dwg, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to field of pharmaceutics and deals with application of film-forming polyurethanes, their mixtures and copolymers in pharmaceutical preparations for dermal or transdermal introduction of active ingredients. Invention also describes applicator, which contains claimed medicine and plaster, which is obtained by application of claimed pharmaceutical preparation.

EFFECT: invention makes it possible to realise dermal or trasdermal introduction of pharmaceutical ingredients with increased degree of penetration.

26 cl, 8 dwg, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine and describes hard drug form in form of decomposing peroral film, which contains (a) food alkaline agent, selected from group including sodium hydroxide, potassium hydroxide, magnesium hydroxide, potassium hydroxide and their mixtures; (b) pharmaceutically effective amount of active ketorophene, ketoprophene pH being brought to the value within the interval from 5.5. to 9; and (c) at least one water-soluble film-generating polymer. Also described is method of claimed film obtaining and its application for reduction or relieving pain.

EFFECT: invention ensures delivery of effective dose of pharmaceutically active ketoprophene to oral cavity without bitter taste sensation and without irritation of oral cavity and larynx mucosa.

17 cl, 7 ex

FIELD: medicine.

SUBSTANCE: claimed invention relates to medicine. Described is composition for transcutaneous absorption of denepezil or its hydrochloride. Composition for transcutaneous absorption includes 2-[(1-benzyl-4-pyperidinyl)methyl]-5,6-dimethoxyindan-1-on and/or its hydrochloride and chloride of metal in layer of adhering under pressure glue preparation, which was subjected to linking.

EFFECT: composition is stable and resistant to loss of cohesive ability of layer adhering with pressure on glue preparation, when applied, and is resistant to adhesive transfer resulting from cohesive destruction during removal by exfoliation.

10 cl, 12 ex

FIELD: medicine.

SUBSTANCE: invention relates to transdermal therapeutic system, which contains, at least, one easily volatile and/or thermolabile biologically active substance and/or auxiliary substance, which can be obtained by limiting on each other of, at least, three components, namely, polymer matrix layer, acceptor layer, absorbing with high speed biologically active substance and/or auxiliary substance, as well as donor-layer, which by the moment of manufacturing contains volatile and/or thermolabile biologically active substance and/or auxiliary substance. During or immediately after lamination process, donor-layer by means of migration of volatile and/or thermolabile substances combines with acceptor layer.

EFFECT: transdermal therapeutic system ensures improved gastrointestinal tolerance.

12 cl, 1 tbl, 1 dwg, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: declared invention refers to chemical-pharmaceutical industry, and concerns 2,2,2-Trifluoro-1-trifluoromethylethyl ester of cyclohexylcarbamine acid which is prepared starting with cyclohexylisocyanate and 1-hydrohexafluorisopropanole at 20°C in benzene in the presence of catalytic amounts of triethylamine.

EFFECT: compound (I) is an effective and selective irreversible carboxylesterase inhibitor with low acute toxicity in warm-blooded, and may be used in preclinical studies on rodents for decreasing carboxylesterase hydrolysis rate of the drugs containing ester and/or amide groups, and also as insect carboxylesterase inhibitors in pharmaceutical composition and pesticide formulations for increasing their efficacy.

2 cl

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of the formula (I) that are characterized by the properties of M3 muscarine receptor antagonist that is applicable in treatment or prevention of the disease or state (the abnormity of) which includes activity of the M3 muscarine receptor such as respiratory diseases. In the formula (I) A is represented by the oxygen atom or the group -N(R12)-; (i) R1 is represented by C1-C6-alkyl or the hydrogen atom; and R2 is represented by the hydrogen atom or the group -R5, -Z-Y-R5, -Z-NR9R10, -Z-NR9CO-R5 or -Z-CO2H; and R3 is absent or is represented by C1-C6-alkyl, and in this case the nitrogen atom to which it is bound is represented by tetradic nitrogen and bears a positive charge; or (ii) R1 and R2 together with nitrogen to which they are bound form heterocycloalkyl ring; the mentioned ring is displaced by the group -Y-R5 or -Z-Y-R5, and R3 is absent or is represented by C1-C6-alkyl, and in this case the nitrogen atom to which it is bound is represented by tetradic nitrogen and bears a positive charge; R4 is represented by the formula group (a), (b), (c) or (d); Z is represented by C1-C16-alkylene group; Y is represented by the link or the oxygen atom; R5 is represented by C1-C6-alkyl, aryl, phenyl condensed with C3-C6cycloalkyl, phenyl condensed with heterocycloalkyl, heteroaryl, aryl(C1-C8-alkyl)-, heteroaryl(C1-C8-alkyl)-, C3-C6cycloalkyl or heteroC3-C6cycloalkyl group; R6 is represented by C1-C6-alkyl or the hydrogen atom; n and m equal 0; R8a and R8b are independently chosen from the group consisting of aryl, phenyl condensed with heterocycloalkyl, heteroaryl, C1-C6-alkyl, C3-C6cycloalkyl; R8c is represented by -OH or C1-C6-alkyl; R9 and R10 are represented independently by the hydrogen atom, C1-C6-alkyl, aryl, phenyl condensed with heterocycloalkyl and other components mentioned in the invention formula.

EFFECT: new compounds applicable in treatment or prevention of the disease or state (the abnormity of) which includes activity of the M3 muscarine receptor such as respiratory diseases.

10 cl, 49 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula representing (2S)-3-(4-cyano-3-fluorphenoxy)-N-(4-cyano-3-methylpheniyl)-2-hydroxy-2-methylpropionamide which exhibits action modulating androgen receptor activity.

EFFECT: production of a pharmaceutical composition and a method of treating or preventing the conditions caused by androgen receptors.

3 cl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel cyclic N,N'-diarylthioureas or N,N'-diarylureas of general formula (1), their optic (R)- and (S)-isomers and their pharmaceutically acceptable salts - antagonists of androgenic receptors. In formula (1), where: X represents oxygen or sulfur atom; m=0 or 1, mR1 represents C1-C3alkyl; R2 and R3 represent hydrogen atom; or R2 and R3 together with carbon atom, to which they are bound, form group C=O; or represents group NH; R4 and R5 represent hydrogen atom; or R4 represents hydrogen atom, and R5 represents methyl; or R4 represents hydrogen atom, methyl, and R5 represents group Zn-Y-R6, in which n=1 or 2, Z represents CH2 or C=0 and Y- oxygen atom or N-CH3, or Y represents C=O, and Z represents CH2; R6 represents hydrogen atom, methyl, benzyl, hydroxygroup or R5 and R4 together with atoms, to which they are bound, form five or sic-member heterocycle, including, at least, oxygen or nitrogen atom, which can be substituted by methyl. Invention also relates to method of obtaining compounds.

EFFECT: invention relates to anti-cancer substance, pharmaceutical composition, medication and method of treating prostate cancer with application of invention compounds.

12 cl, 6 dwg, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound, represented by the following formula (I), where R represents hydrogen atom or P(=O)(OH)2, X represents oxygen atom or sulphur atom, Y represents CH2CH2 or CH=CH, R1 represents trifluoromethyl, difluoromethyl or cyano, R2 represents alkyl, which has 1-4 carbon atoms, and optionally substituted with hydroxyl group (groups) or halogen atom (atoms), R3 and R4 can be similar or different, and each represents hydrogen atom or alkyl, which has 1-4 carbon atoms, and n=5-8, or its pharmaceutically acceptable acid-additive salt. Invention also relates to 2-amino-2-[2-(4-heptyloxy-3-trifluoromethylphenyl)ethyl]propan-1,3-diol or its hydrochloride and pharmaceutical composition, containing said compounds.

EFFECT: elaboration of pharmaceutical composition, applied for treatment or prevention of autoimmune diseases, prevention or suppression of resistance or acute rejection or chronic rejection of organ or tissue transplant; treatment or prevention of graft-versus-host disease (GvH) resulting from transplantation of bone marrow; or treatment or prevention of allergic diseases.

16 cl, 39 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an ester presented by formula [2] where R1' represents 1) C1-C6 alkyl which is optionally substituted by one or more identical or different halogens, or 2) -CO-C1-C6 alkoxy; R2' represents 1) hydrogen or 2) C1-C6 alkyl, R3', R4' and R5' are identical or different, and each represents 1) hydrogen, 2) halogen, 3) C1-C6 alkyl which is optionally substituted by one or more identical or different halogens, 4) C1-C6 alkoxy, 5) -COR13' where R13' represents (a) hydroxy, (b) C1-C6 alkyl, (c) C1-C6 alkoxy which is optionally substituted by one or more identical or different substitutes selected from (1) hydroxy, (2) C1-C6 alkoxy which is optionally substituted by phenyl, (3) -NR11'CO-C1-C6 alkyl where R11' represents hydrogen, (4) -CONR8'R9' where R8' and R9' are identical or different, and each represents C1-C6 alkyl, (5) -CO- C1-C6 alkoxy optionally substituted by phenyl, (6) phenyl optionally substituted by one or more identical or different substitutes selected from halogen, C1-C6 alkoxy and -CO-C1-C6 alkoxy, and (7) a heterocycle selected from pyridyl, thienyl and which all can be substituted by one or more identical or different C1-C6 alkyl groups, or (d) -OR19' where R19' represents a group or a group or piperidyl which is optionally substituted by -CO-C1-C6alkyl, 6) a heterocycle selected from oxadiazolyl and tetrazolyl, and said heterocycle is optionally substituted by C1-C6 alkyl optionally substituted by one or more identical or different substitutes selected from -CONR8'R9' (R8' and R9' have the same values as defined above) and -CO-aralkyloxy, or 7) nitrile; R6' and R7' are identical or different, and each represents 1) C1-C6 alkyl or 2) a nitrogen-containing 5 or 6-members saturated heterocycle containing a monocycle formed when R6', R7' and a neighbouring nitrogen atom are taken together, and optionally including oxygen as a heteroatom; Y1, Y2, Y3 are identical or different, and represent, 1) all carbon atoms, or 2) one of Y1, Y2, Y3 represent a nitrogen atom, and the others are carbon atoms; Y4 represent a carbon or nitrogen atom ;-X- represents 1) -(CH2)1 where 1 represents an integer 1 to 3, 2) -CH2-NR18'-CH2- where R18' represents C1-C6 alkyl, or 3) or to its pharmaceutically acceptable salt.

EFFECT: compounds presented by formula are effective as agents for treatment or prevention hyperlipidemia, arteriosclerosis, coronary artery disease, obesity, diabetes and hypertension or similar diseases since they are withdrawn very quickly and exhibit excellent MTP inhibitory activity.

23 cl, 32 tbl, 137 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an ester presented by formula [2] where R1' represents 1) C1-C6 alkyl which is optionally substituted by one or more identical or different halogens, or 2) -CO-C1-C6 alkoxy; R2' represents 1) hydrogen or 2) C1-C6 alkyl, R3', R4' and R5' are identical or different, and each represents 1) hydrogen, 2) halogen, 3) C1-C6 alkyl which is optionally substituted by one or more identical or different halogens, 4) C1-C6 alkoxy, 5) -COR13' where R13' represents (a) hydroxy, (b) C1-C6 alkyl, (c) C1-C6 alkoxy which is optionally substituted by one or more identical or different substitutes selected from (1) hydroxy, (2) C1-C6 alkoxy which is optionally substituted by phenyl, (3) -NR11'CO-C1-C6 alkyl where R11' represents hydrogen, (4) -CONR8'R9' where R8' and R9' are identical or different, and each represents C1-C6 alkyl, (5) -CO- C1-C6 alkoxy optionally substituted by phenyl, (6) phenyl optionally substituted by one or more identical or different substitutes selected from halogen, C1-C6 alkoxy and -CO-C1-C6 alkoxy, and (7) a heterocycle selected from pyridyl, thienyl and which all can be substituted by one or more identical or different C1-C6 alkyl groups, or (d) -OR19' where R19' represents a group or a group or piperidyl which is optionally substituted by -CO-C1-C6alkyl, 6) a heterocycle selected from oxadiazolyl and tetrazolyl, and said heterocycle is optionally substituted by C1-C6 alkyl optionally substituted by one or more identical or different substitutes selected from -CONR8'R9' (R8' and R9' have the same values as defined above) and -CO-aralkyloxy, or 7) nitrile; R6' and R7' are identical or different, and each represents 1) C1-C6 alkyl or 2) a nitrogen-containing 5 or 6-members saturated heterocycle containing a monocycle formed when R6', R7' and a neighbouring nitrogen atom are taken together, and optionally including oxygen as a heteroatom; Y1, Y2, Y3 are identical or different, and represent, 1) all carbon atoms, or 2) one of Y1, Y2, Y3 represent a nitrogen atom, and the others are carbon atoms; Y4 represent a carbon or nitrogen atom ;-X- represents 1) -(CH2)1 where 1 represents an integer 1 to 3, 2) -CH2-NR18'-CH2- where R18' represents C1-C6 alkyl, or 3) or to its pharmaceutically acceptable salt.

EFFECT: compounds presented by formula are effective as agents for treatment or prevention hyperlipidemia, arteriosclerosis, coronary artery disease, obesity, diabetes and hypertension or similar diseases since they are withdrawn very quickly and exhibit excellent MTP inhibitory activity.

23 cl, 32 tbl, 137 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds - arylamidrazone derivatives of formula ,

where R1 is a C2-C8 alkyl group or a C2-C8 alkoxy group, which can be substituted with a halogen or a C1-C8 alkoxy group; a 5-7-member aromatic heterocycle containing 1 or 2 oxygen, nitrogen or sulphur atoms, or phenyl, which can be substituted with a halogen, a C1-C8 alkyl group, a haloC1-C8alkyl group or a C1-C8alkoxy group; or NR4R5; R2 and R3 are identical or different, and each is a hydrogen atom, a halogen atom, a halogenC1-C8alkyl group, a C1-C8alkyl group, a C2-C6alkynyl group, a C1-C8alkoxy group, a cyano group, a C2-C6alkanoyl group or a C1-C8alkylsulphonyl group; A is a benzene, pyridine, quinoline or isoquinoline ring; D is a single bond or methylene; m assumes values from 1 to 3 and n assumes values from 1 to 5, having antagonistic effect on S1P3 receptors, as well as to medicinal agents and pharmaceutical compositions containing such compounds as an active ingredient.

EFFECT: improved properties.

13 cl, 161 ex, 19 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel pharmaceutic applications of compounds acting as mGluR5 antagonist, for treatment, prevention and/or delay of progressing of disorders of gastrointestinal tract, urinary tract and/or post-operation disorders, as well as for treatment, prevention and/or delay of progressing of pain associated with said disorders.

EFFECT: said purpose is realised.

10 cl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I), optical isomers or pharmaceutically acceptable salts thereof which can be used to inhibit or block reuptake of 5-hydroxytryptamine (5HT) and/or norepinephrine (NA), as well as for treating diseases associated with the central nervous system, a pharmaceutical composition based on said compounds and use thereof in preparing a medicinal agent. (I), where the chiral centre (*) can be R or S or RS (racemic mixture), R3 and R4 are independently selected from saturated alkyl, having 1-6 carbon atoms, and R1 and R2 are as described in the formula of invention.

EFFECT: high effectiveness of the compounds.

12 cl, 10 tbl, 3 dwg, 15 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine and pharmaceutical industry, namely to composition for transcutaneous delivery of medication, which is realised from mixture, which contains: therapeutically efficient amount of medication, including initial medication and promedicine, as well as pharmaceutically acceptable carrier, both initial medication and promedicine being present in amount sufficient for manifestation of pharmacologic activity.

EFFECT: in preferable version of invention implementation mixture includes therapeutically efficient amount of pharmaceutically active agent, which contains ACE inhibitor, such as ramipril, promedicine being promedicine of ACE inhibitor, such as ethyl ester of ramipril and/or methyl ester of ramipril.

5 cl, 10 ex, 9 dwg

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