Delayed release pill containing reboxetin

FIELD: medical engineering.

SUBSTANCE: pill taken per os comprises pharmaceutically active agent selectable from (S,S)-Reboxetin or its salt and Pramipexol or its salt. The pharmaceutically active agent is taken in the amount of 0.01% by mass to 25% by mass of composition. It is dispersed in matrix composed of hydrophilic polymer and starch having rupture strength of at least approximately 0.15 kN·cm-2, at least approximately 0.175 kN·cm-2 or at least approximately 0.2 kN·cm-2, when having solid substance usable for producing pills where hydrophilic polymer takes approximately 20-70% by mass and starch is available in the amount of approximately 25-75% by mass. Method involves determining starch usability and composition applicability for treating the cases of disorders and states selected from depressive psychosis, neuropathic pains and Parkinson disease. Starch of specified rupture strength allows pill to withstand high speed pelletization operation and to provide prolonged drug release and to take a pill once a day.

EFFECT: controlled and prolonged drug action; enhanced effectiveness of treatment.

21 cl, 9 tbl

 

The technical field to which the invention relates.

The present invention relates to compositions for tablets and more specifically to compositions tablet delayed release for oral delivery of water-soluble drugs or prodrugs.

Background of invention

Many active pharmaceutical agents, including drugs and prodrugs, are delivered as oral dosage form providing delayed release (otherwise known as a slow release or sustained release) of such funds during the period of time, allowing you to enter the tool once a day. A well-known system for the preparation of such dosage forms includes a matrix containing a hydrophilic polymer, which dispersed the tool; the tool is released for a certain period of time in the gastrointestinal tract after dissolution or destruction of the matrix. Dosage forms with delayed release containing this matrix system, usually obtained in the form of compressed tablets, called in this case "matrix tablets".

Drugs and prodrugs having a relatively high solubility in water, for example a solubility of about 10 mg/ml or pain is th, determine the necessity of creation of dosage forms with delayed release, and the higher the solubility, the more necessitous such a need. As an example of such necessary, you can lead the pramipexole dihydrochloride, having a solubility in water of about 200 mg/ml, and reboxetine mesilate, having a solubility in water of about 250 mg/ml

Pramipexol (I) is an agonist of the dopamine receptor D2applicable in the treatment of Parkinson's disease. Pramipexol as its dihydrochloride salt, in the United States is available commercially in the form of tablets Mirapex® from Pharmacia & decision Upjohn. These tablets are tablets with immediate-release formulation containing 0.125 mg, 0.25 mg, 0.5 mg, 1.0 mg and 1.5 mg of active tools designed for oral administration one tablet three times daily with providing a daily dose of 0,375-4,5 mg. Cm. Physicians' Desk Reference, 57th edition (2003), 2768-2772. In this case the dose is expressed in quantities monohydrate dihydrochloride pramipexole, unless otherwise indicated; 1.0 mg of the monohydrate of pramipexole dihydrochloride equivalent to about 0.7 mg pramipexole base

The regimen of medicines three times a day for the tablets with immediate-release pramipexole dihydrochloride well tolerated, but patients ' adherence to semiprime can be greatly improved, if it was possible scheme with a single reception. In this regard it should be noted that the main indication for this medication, Parkinson's disease, is a disease that is becoming common with age and is often accompanied by memory impairment. Receive mode once a day is particularly suitable for enhancing the adherence of the admission medication among elderly patients.

The authors of the present invention have found that the composition with the monohydrate of pramipexole dihydrochloride in the tablet with hydrophilic matrix, as a rule, does not meet the requirements to provide slow release properties, consistent with the dose once a day. Characteristics can also be changed, causing the tablet coating for sustained release. This coating usually contains a hydrophobic polymer and a hydrophilic pore-forming.

The need to apply the coating to a matrix tablet causes other problems. Additional operations to be included at the stage of coating, require that the tablet was firm enough to prevent damage and/or abrasion during such operations, particularly in conditions of high-speed processing.

Reboxetine (II) is a selective inhibitor of obratno the capture of noradrenaline (SNRI), suitable in the treatment of depressive disorders. Reboxetine as its methanesulfonate salt (mesilate), commercially available in the UK and other countries in the form of tablets Edronax® from Pharmacia & decision Upjohn. Such tablets are tablets with immediate-release notch for breaking easy division. Each tablet of edronax® contains 4 mg of reboxetine and designed for oral administration twice a day to ensure a daily dose of 4-12 mg, division pills if necessary. Cm. British National Formulary, 41st edition (2001), 196. In this case, the doses are expressed in quantities of reboxetine basis, unless otherwise specified

Regimen medicines twice a day for tablets with immediate-release reboxetine well tolerated, but patients ' adherence to regimens can be much improved if it were possible scheme with a single reception without a significant increase possible side effects. In this regard it should be noted that the main indication for this medication, depressive disorder, is a disease that is often accompanied by violation of the reception mode.

The authors of the present invention have found that a composition containing salts of reboxetine in the tablet with hydrophilic matrix may provide the given properties of a slow-release, consistent with the dose once a day. However, the resulting tablets are sensitive to erosion and/or abrasion during handling, especially at high speed tabletting operations.

It is proved that it is difficult to get a tablet with a suitable combination of slow release properties and machinability, where the medicinal product is a product with a relatively high solubility, as in the case of salts of pramipexole and reboxetine.

In U.S. patent No. 6197339 revealed tablet delayed release containing Z-2-butenedioate (R)-5,6-dihydro-5-(methylamino)-4H-imidazo[4.5-ij]quinoline-2(1H)-she (1:1) (maleate of sumanirole) matrix containing hypromellose (receiver array) and starch. It is reported that the tablet is suitable for the treatment of Parkinson's disease. It is reported that appropriate in this case starches include pre gelatinizing starch.

In U.S. patent No. 5458887 revealed tablet with controlled release formulation containing an osmotic core, consisting of a medicinal product in a mixture with swelling in water component, such as a receiver array, or polyethylene oxide, and the coating containing water-resistant polymer and a small amount of water-soluble compounds, which acts as a blowing agent. It is reported that after the formation of pores in the coating due to rest the rhenium water-soluble substance, swelling in water, increases the core and provides a contact surface that is enriched with a therapeutic environment in the gastrointestinal tract.

In U.S. patent No. 5656296 disclosed dual tablet with controlled and delayed release containing a core containing a drug and low-melting filler, and the coating layer on the core containing the pH-independent water-insoluble polymer and a water-soluble film-forming polymer.

In the application for European patent number EP 0933079 disclosed starch, reported that it is suitable to obtain tablets with high hardness, but also can quickly spread in the aquatic environment. The tensile strength of the final tablets calculate the hardness.

Patents and publications, cited above, included in the present description as a reference.

The object of the present invention is a composition for tablets with delayed release of water-soluble drugs or prodrugs suitable for oral administration once per day. Another purpose is to such a composition having sufficient hardness to withstand high-speed tabletting operation, in particular to resist erosion during coating. Another purpose is a pharmaceutical tablets is ka, providing long-term therapeutic effect on the Central nervous system (CNS) of the subject with the introduction of once per day. The specific purpose is such tablet that provides long-term therapeutic action as a dopamine agonist in the introduction, once a day, especially where water-soluble drug is a salt of pramipexole, no significant increase in the incidence of side effects. Another specific purpose is such tablet that provides a therapeutic effect as SNRI with the introduction of once a day, especially where water-soluble drug is a salt of reboxetine or its enantiomer, for example (S,S)-reboxetine, no significant increase in the incidence of side effects. Another purpose is a method of testing starch to assess its suitability for inclusion in the matrix tablet for sustained release of water soluble drugs or prodrugs.

Summary of the invention

The present invention relates to pharmaceutical compositions in the form of tablets that are delivered orally, contains an active pharmaceutical agent with a solubility of not less than about 10 mg/ml, dispersed in the matrix containing a hydrophilic polymer and a starch having a strength h is the gap in the share of solids, typical for tablets, at least about 0.15 kN·cm-2. The composition preferably detects the slow release properties, appropriate therapeutic efficacy when administered orally no more than once per day to a subject in need of it.

The invention also relates to a method for producing a pharmaceutical composition with delayed release in the form of tablets that are delivered orally, including by appropriate tests starch having a tensile strength percentage solids, typical tablets, at least about 0.15 kN·cm-2; mixing with the selected starch hydrophilic polymer and an active pharmaceutical agent with a solubility of not less than about 10 mg/ml to obtain a mixture, where the tool dispersed in the matrix containing the polymer and starch; and compressing the mixture to form tablets.

A particularly convenient method of testing, which is itself another embodiment of the invention, includes obtaining briquettes sample of starch in tablet press machine in the interval compressive efforts, the measurement of the hardness of the pellets, measuring the proportion of solids in the briquettes, the computation of the tensile strength of the briquettes from the hardness and size of the briquettes, the definition of the relationship of tensile strength to share solids breaketh and evaluation of the obtained relationship of tensile strength with a share of solids, characteristic for the desired tablets.

The invention also relates to a method of treatment of a subject having a condition or disorder, in which is shown an active pharmaceutical agent having solubility not less than about 10 mg/ml, comprising oral administration of the subject compositions with delayed release of the drug in the form of tablets containing agent, dispersed in the matrix containing a hydrophilic polymer and a starch having a tensile strength percentage solids, typical tablets, at least about 0.15 kN·cm-2.

In this case, "active pharmaceutical agent" can be a drug or prodrug, or salt, including diagnostic tools. Unless otherwise specified, in this specification, the "solubility" means a solubility in water at 20-25°at any physiologically acceptable pH, for example at any pH in the range of from about 4 to about 8. In case the funds, representing salt, a reference to the solubility refers to salt, but not a means in the form of free acid or free base.

In this description, the term "deliver oral" means suitable for oral, including oral and intra-oral (e.g., sublingual or buccal), but tablets is altoadige of the invention are adapted mainly for oral administration, i.e. for ingestion, typically, whole or broken, with the help of water or other potable liquid.

In this description, "briquette" represents a pressed tablet, obtained, for example, on a tablet press, consisting only of the sample of starch for which you want to measure the tensile strength. "The proportion of solids" is the ratio of the absolute density of the briquette to apparent density. "The proportion of solids", typical tablets, represents the proportion of solids is selected as a similar proportion of solids of tablets obtained according to the invention. Typically will be selected fraction of solids tablets from about 0.75 to about 0.85 are for example 0,8.

In this description of the "subject" is an animal of any species, preferably a mammal, most preferably a human. The condition and disorder of the subject, which in this case is "shown" some means, not limited to conditions and disorders for which the specified tool approved by the Supervisory authority, but also include state and disorders that doctors know, or assume that they are treatable with the specified tool. "Treatment" in this case covers preventive treatment, unless the context trail is t otherwise.

Brief description of drawings

Fig. 1 is a graph showing the ratio of the tensile strength of the parties pre-gelatinizing starch when determining the test method according to the invention using the dwell time in the mold under pressure 4 seconds (example 1 of this specification) and the uniaxial tensile strength.

Fig. 2 is a graph showing the ratio of the tensile strength of the parties pre-gelatinizing starch when determining the test method according to the invention using the dwell time in the mold under pressure for 90 seconds (example 1 of this specification) and the uniaxial tensile strength.

Fig. 3 is a graph showing the correlation between the tensile strength of the parties pre-gelatinizing starch with a maximum hardness of tablets containing these parties.

Fig. 4 is a graph showing the dissolution profiles in vitro three different compositions of tablets with delayed release 0.375 mg of the monohydrate of pramipexole dihydrochloride, which is described in detail in example 10.

Fig. 5 is a graph showing the dissolution profiles in vitro three different compositions of tablets with delayed release 4 mg (S,S)-reboxetine in the form of its succinate salt, which is described in detail in example 12.

Detailed description the s inventions

The invention relates to pharmaceutical compositions in the form delivered oral tablet containing a water-soluble pharmaceutical agent. The composition preferably exhibits properties of a slow-release drugs, adequate to ensure therapeutic efficacy when administered orally no more than once per day.

As a rule, the funds for which the invention is particularly suitable, not suitable for a single injection per day, when included in the composition with the immediate-release medications. Such inadequacies can occur because one or more properties of such funds, including, without limitation,

(a) short-time existence (T1/2) or its active metabolite in the bloodstream, requiring that to maintain therapeutically effective plasma concentration of its "fed" through periods shorter than one day;

(b) the possible unwanted side effects that arise because of the high plasma concentrations (Cmax) or its therapeutically active metabolite.

Relatively few facilities having solubility not less than about 10 mg/ml, are medicationonline connections. The majority represents the connections that exist is the form of the free acid or free base present in the composition according to the invention in such form or often, in the form of pharmaceutically acceptable salts. The solubility of the preferred means is not less than about 50 mg/ml, preferably not less than about 100 mg/ml For the purposes of the present invention means are classified in United States Pharmacopeia, 14th edition (2000) (USP 24) as "fully soluble" or "unlimited soluble", are considered as having solubility not less than about 100 mg/ml, and together with the funds which are classified in USP 24 as "soluble" or "sparingly soluble", are considered as having solubility not less than about 10 mg/ml

Active pharmaceutical agents suitable in this case, it can be any therapeutic categories, such as any of therapeutic categories listed in The Merk Index, 13th edition (2001). A partial list of tools that are suitable in this case, is given below to illustrate with the remark that, when lists one or more salts funds, other pharmaceutically acceptable salts with a solubility of not less than about 10 mg/ml ("similar salts") may be replaced.

Sulfate abacavir

Acarbose

Hydrochloride acebutolol

Calcium salt of acetylsalicylic acid

Acyclovir sodium

Sulfate albuterol

Alendronate sodium

Hydrochloride Alfentanil

Maleate of almotriptan

Hydrochloride alosetron

Hydrochloride amantadine

Amdinocillin

Hydrochloride aminolevulinic acid

Aminophylline

Salt p-aminosalicylate calcium, sodium and potassium

Hydrochloride amitriptyline

Salts are the acetate, hydrochloride and amlodipine mesilate

Salt phosphate and sulfate of amphetamine

Arbutamine

Atenolol

Atropine sulphate

Azlotillin sodium

Balsalazide disodium

Hydrochloride of benazepril

Mesilate of benztropine

Chloride bethanechol

The fumarate bisoprolol

Maleate of brompheniramine

Hydrochloride bupropion

Caffeine and caffeine citrate

Capecitabine

Captopril

Carbenicillin disodium

Citrate carbetapentane

Maleate carbinoxamine

Cefaclor

Cefmetazole sodium

Cefodizime disodium

Ceftezole sodium

Ceftiofur sodium

Ceftriaxone disodium

Cefuroxime sodium

Carusona sodium

Hydrochloride cetirizine

Hydrochloride cevimeline

Hydrochloride chlordiazepoxide

Phosphate chloroquine

Maleate chlorpheniramine

Hydrochloride chlorpromazine

Cilastatin sodium

Hydrochloride, cimetidine

Hydrochloride clindamycin

Phosphate clindamycin

Hydrochloride clomipramine

Hydrochloride clonidine

Clorazepate of dItalia

Salt is the hydrochloride and sulfate codeine

Codeine phosphate

Hydrochloride of cyclobenzaprine

Guide klorid ciprogeptadina

Hydrochloride group probably facilitates

Hydrochloride, daunorubicin

Hydrochloride, desipramine

Dexamethasone-21-phosphate disodium

The hydrobromide of dextromethorphan

Dibekacin

Diclofenac potassium

Dicloxacillin sodium

Hydrochloride dicyclomine

Didanosine

Dihydrocodeine

Hydrochloride diltiazem

Hydrochloride diphenhydramine

Disulfiram

Mesilate of bolasterone

Hydrochloride donepezil

Hydrochloride dopamine

Hydrochloride dorzolamida

Hydrochloride of doxepin

Gilat (hyclate) doxycycline

Hemisulfate of eletriptan

Maleate enalapril

Hydrochloride of epinastine

Salt glucoheptonate and lactobionate erythromycin

Ethosuximide

Heteronomy acid and sodium salt

Hydrochloride of etoperidone

Hydrochloride fadrozole

Famciclovir

Fentanyl citrate

Fluctin

Phosphate fludarabine

Hydrochloride fluoxetine

Fluvastatin sodium

Fosfomicin and vospominanyami

Poposal

Fosinopril sodium

Fosphenytoin disodium

Succinate of frovatriptan

Gabapentin

Gatifloxacin

Glycopyrrolate

Hydrochloride granisetron

Guaifenesin

Hydrochloride, haloperidol

Gatroenterology

Hydrochloride hydralazine

Salt bitartrate hydrochloride and hydrocodone

Hydrochloride hydromorphone

The dihydrochloride hydroxyzine

The hydrobromide giostsiamina

Of imatinib mesilate

Hydrochloride imipramine

Encadrant disodium

Sulfate indinavir

Isoniazid

Hydrochloride of isoxsuprine

Chloroethylamine

Hydrochloride labetalola

Lamivudine

Levamisole hydrochloride

Levitiracetam

Hydrochloride lidocaine

Lisinopril

Losartan potassium

Acetate mafenide

Hydrochloride mecamylamine

Hydrochloride of medetomidine

Miglitol

Hydrochloride meperidine

Bitartrate metaraminol

Hydrochloride Metformin

Hydrochloride methadone

Hydrochloride methamphetamine

Methenamine

Methimazol

The bromide methscopolamine

Hydrochlorothiazide methyldopa

Hydrochloride methylphenidate

Methylprednisolone-21-sodium succinate

Metoclopramide

Succinate metoprolol

Hydrochloride metralindol

Hydrochloride meksiletina

Mezlocillin sodium

Hydrochloride midazolam

Hydrochloride midodrina

Miglitol

Mizoribine

Hydrochloride moeksiprila

Hydrochloride molindone

Montelukast sodium

Morphine hydrochloride

Morphine sulfate

The salicylate of research

Hydrochloride of nalmefene

Hydrochloride naloxone

Naproxen sodium

Hydrochloride naratriptan

Nedocromil disodium

Salt bromide and methyl sulfate of neostigmine

Nitrofurantoin

Nizatidine

Hydrochloride nortriptyline

Ofloxacin

Olsalazine sodium

Hydrochloride ondansetron

Hydrochloride of orphenadrine

Hydrochloride of oxibutinina

Hydrochloride oxycodone

Pantoprazole sodium

Parecoxib sodium

Pemirolast potassium

Penicillamine

The sodium and potassium salts of penicillin G

Penicillin V potassium

Izational of pentamidine

Pentobarbital sodium

Pentosanpolysulfate sodium

Pentoxifylline

Perindoprilat

Tartrate of phendimetrazine

Of phenelzine sulfate

Hydrochloride phenoxybenzamine

Hydrochloride phentermine

Hydrochloride phenylephrine

Hydrochloride phenylpropanolamine

Phenytoin sodium

Citrate phenyltoloxamine

Pidotimod

Hydrochloride pilocarpine

Piperacillin sodium

The dihydrochloride pirenzepine

The pramipexole dihydrochloride

Pravastatin sodium

Phosphate prednisolone sodium

Hydrochloride procainamide

Procarbazine hydrochloride

Procodazole

Hydrochloride prometazina

Hydrochloride propacetamol

Hydrochloride propoxyphene

Hydrochloride propranolol

Hydrochloride of protriptyline

Hydrochloride pseudoephedrine

Bromide mestinon

Hemifumarate of quetiapine

Hydrochloride inapril

G is ukeat quinidine

Quinine bisulfate

Rabeprazole sodium

Raltitrexed

Hydrochloride ramosetron

Hydrochloride ranitidine

Salt mesilate and reboxetine succinate

Ribavirin

Rimantadine hydrochloride

Risedronate sodium

The rivastigmine tartrate

Benzoate of rizatriptan

Hydrochloride ropinirole

The hydrobromide of scopolamine

Hydrochloride selegilina

Hydrochloride sotalol

Stavudine

Sulbenicillin disodium

Sulfacetamide sodium

Maleate of sumanirole

Succinate sumatriptan

Hydrochloride of tacrine

Taurolidine

Hydrochloride terazosin

Hydrochloride tetracycline

Acetate theobromine sodium salicylate theobromine sodium

Defininately and theophyllinetriazolam

Acetate of theophylline sodium and glycinate theophylline sodium

Hydrochloride thioridazine

Thyroxine sodium

Hydrochloride, ticlopidine

Maleate timolol

Tartrate tolterodine

Hydrochloride tramadol

Hydrochloride trientine

The trifluoperazine dihydrochloride

Hydrochloride valacyclovir

Hydrochloride of valganciclovir

Valproate sodium

Hydrochloride venlafaxine

Hydrochloride verapamil

Warfarin sodium

Zolmitriptan

Hemitartrate zolpidem

Other means suitable in this case are N-[5-(1,4-diazepan-1-yl)-2-[(3-forfinal)Sul is of IMT]phenyl]acetamide", she N-[(3R)-1-azabicyclo[2.2.2]Oct-3-yl]furo[2,3-C]pyridine-5-carboxamide and their salts.

It should be borne in mind that the indication of the active pharmaceutical agent in this case covers its racemates, enantiomers, polymorphs, hydrates and solvate.

The present invention is particularly suitable for strong drugs and prodrugs, for example, those that are therapeutically effective in small daily doses, for example, not greater than about 100 mg/day, particularly not greater than about 50 mg/day, preferably not greater than about 25 mg/day, even more preferably not greater than about 10 mg/day and most preferably not greater than about 5 mg/day.

In one embodiment, the active pharmaceutical agent has a therapeutic effect on the Central nervous system (CNS). These funds, referred to in this description of "Central nervous system-tools", suitable for the treatment or prevention of disorders of the Central nervous system and include, without limitation, anti-convulsants, antidepressants, anti-psoriasis, anti-epileptics, anti-mania, anti-migraine, blockers, muscarinic receptors, antiobsessive tools, anti-parkinsonism, antipsychotics, antispasmodic, anxiolytic drugs, cholinergic tools, amphetamines is ora CNS, the dopamine receptor agonists, dopamine receptor antagonists, hypnotics, monoamine oxidase inhibitors, neuroleptics, neuroprotective agents, antagonists of NMDA receptors, nootropic agents, inhibitors of prolactin, sedatives, selective serotonin reuptake inhibitors serotonin selective reuptake inhibitors of norepinephrine, which reduces the aggressiveness means, agonists of serotonin receptors, antagonists of serotonin receptors and tranquilizers.

For clarification, the Central nervous system-tools usable in this case include the salts of sumanirole, reboxetine and pramipexole.

Sumanirole preferably used in the form of the R-enantiomer (R)-5,6-dihydro-5-(methylamino)-4H-imidazo[4.5-ij]quinoline-2(1H)-she (III), which can be replaced by its tihonovym analogue of (R)-5,6-dihydro-5-(methylamino)-4H-imidazo[4.5-ij]quinoline-2(1H)-tion (IV)

In the case of compound (III) or (IV) suitable salts are the salts are hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, maleate, malate, succinate, tartrate, cyclohexanesulfamic, mesilate (methanesulfonate), Eilat (econsultant), besilate (bansilalpet) and tosylate (p-toluensulfonate). The preferred salt is a maleate.

Song sumanirole according to the invention are suitable for administration no more than DV is x times per day, preferably no more than once per day. Such compositions are suitable for the treatment of any condition or disorder of the CNS, in which case sumanirole therapeutic suitability, but especially in the case of Parkinson's disease and its related complications.

Reboxetine (II) can be used in the form of a racemic mixture containing two or more enantiomers of (R,R)-reboxetine, (S,S)-reboxetine, (R,S)-reboxetine and (S,R)-reboxetine, or in the form of any one of these enantiomers. Preferably use (S,S)-reboxetine.

Suitable salts of reboxetine salts are hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, acetate, propionate, lactate, maleate, malate, succinate, fumarate, tartrate, cyclohexanesulfamic, mesilate, Eilat, besylate and tosylate. In the case of the racemate reboxetine preferred salt is a maleate. In the case of (S,S)-reboxetine preferred salts are salts of succinate and fumarate, especially succinate.

Compositions with reboxetine and (S,S)-reboxetine according to the invention is preferably suitable for administration not more than once per day. Such compositions are suitable for treating a condition or disorder of the CNS, in which case reboxetine and its enantiomers have therapeutic usefulness, but in particular in the case of depressive illness and neuropathic pain is, including post herpetic neuralgia and diabetic neuropathy.

Pramipexol (I) is used preferably in the form of its S-enantiomer (S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)-benzothiazole. The preferred salt of pramipexole is the dihydrochloride, most preferably, in the form of a monohydrate.

Compositions with pramipexol according to the invention is preferably suitable for administration not more than once per day. Such compositions are suitable for treating a condition or disorder of the CNS, in which case pramipexol has therapeutic fitness, but particularly in the case of Parkinson's disease and its related complications.

All active pharmaceutical agents suitable in this case, can be obtained by methods known in themselves, disclosed in patents and other literature relating to specific agents of interest.

The number of active pharmaceutical agent present in the composition according to the invention depends on the strength of the agent, but is sufficient to provide a daily dose while introducing one to a small number, for example from one to about 4 tablets. Preferably, the total daily dose is delivered in a single tablet. In most cases, the amount of agent in the tablet is from about 0.1 to about 200 mg,preferably from about 0.2 to about 100 mg. Expressed in percent by weight of the composition, the amount of agent typically ranges from about 0.01% to about 25%, preferably from about 0.05% to about 20%. If the agent representing the salt, the amount of agent in this description is expressed as an equivalent amount of free acid or free base, unless otherwise indicated.

For clarification, in the case of sumanirole appropriate, will generally be a number from about 0.5 to about 25 mg per tablet or from about 0.1 wt.% to about 15 wt.% from the composition. Specific dosage on the pill, the alleged herein, include 0,5, 1, 2, 4, 8, 12 and 24 mg sumanirole in the form of the maleate of sumanirole.

In the case of pramipexole appropriate, will generally be a number from about 0.1 to about 10 mg per tablet or from approximately 0.05 wt.% to about 5 wt.% from the composition. Preferably, there is a number of from about 0.2 to about 6 mg, preferably an amount of from about 0.3 to about 5 mg of pramipexole on the tablet. Specific dosage on the pill, the alleged herein, include 0,375, 0,5, 0,75, 1,0, 1,5, 3,0 and 4.5 mg of the monohydrate of pramipexole dihydrochloride.

In the case of reboxetine or (S,S)-reboxetine appropriate, will generally be a number from about 0.2 to about 15 mg per tablet, or from about 0.1 wt.% up to about 10 wt.% from the comp the positions. Preferably, there is a number of from about 1 to about 12 mg of reboxetine or (S,S)-reboxetine on the tablet. Specific dosage on the pill, the alleged herein, include 1, 2, 4, 6, 8, and 12 mg of reboxetine in the form of its salts or nelfinavir (S,S)-reboxetine in the form of its succinate salt.

The composition of the present invention includes an active pharmaceutical agent, as stated above, dispersed in the matrix containing a hydrophilic polymer and a starch having a tensile strength of at least approximately 0.15 kN·cm-2with a share of solids, typical tablets, for example, from about 0.75 to about 0.85 are for example 0,8.

Hydrophilic polymers suitable in this case are the pharmaceutically acceptable polymeric materials having a sufficient number and distribution of hydrophilic substituents, such as hydroxy - and carboxypropyl, which imparts hydrophilic properties to the polymer as a whole. Suitable hydrophilic polymers, without limitation, are methylcellulose, a receiver array (hypromellose), carmelitani (carboxymethylcellulose) and carbomer (polyacrylic acid). You can use optional, a few of these polymers.

A receiver array is the preferred hydrophilic polymer. Available in various receiver array and with different degree of substitution. In one embodiment the use of the comfort type 2208 receiver array, preferably, satisfies the requirements of the specifications listed in the standard pharmacopoeias, such as USP 24. Type 2208 receiver array contains 19-24 wt.% methoxy and 4-12 wt.% hydroproportional. Especially suitable receiver array have a viscosity ranging from about 100 to about 10,000 MPa·with; for example, a suitable receiver array type 2208 is a receiver array with a nominal viscosity of about 4000, with the measured viscosity of from about 3000 to about 56000 MPa·C. Such a receiver array is available, for example, as metozel® KMR from Dow Chemical Co., and essentially equivalent products are available from other isotopically.

The amount of hydrophilic polymer in the composition depends on the specific polymer, the active pharmaceutical agent and the desired slow release profile. However, typically, the hydrophilic polymer include from about 20% to about 70%, preferably from about 30% to about 60% and preferably from about 35% to about 50%, by weight of the composition. In the case given as an example of a receiver array type 2208 appropriate amount will typically be in the range of from about 30% to about 60%, preferably from about 35% to about 50%, for example in an amount of about 40%, by weight of the composition.

It is assumed, without going into theory that the function of the hydrophilic polymer which provide the military or delayed release of the active pharmaceutical agent, for example, due to the gradual dissolution or erosion of the polymer in the gastrointestinal tract.

Starches suitable in this case, include starches from any vegetable source, such as corn, wheat, rice, tapioca, potato, etc. Preferred starches have a relatively high ratio of amylose to amylopectin and contain, for example, at least about 20%, preferably at least about 25%amylose. Especially preferred is a pre-gelatinizing starch, representing a type of modified starch, processed with the goal of making the starch more fluidity and direct compressibility. You can use partially or fully pre-gelatinisation starches.

It is assumed, without going into theory that the main function of starch in the composition of the invention is its function as a binder. Starch, satisfying the criterion of tensile strength specified in this description can be called "superclasses".

The amount of starch in the composition is typically higher than the usual amount as binders in the compositions of the tablets. The appropriate amount will typically be in the range of from about 25 wt.% to about 75 wt.%. Preferably, the amount of starch is from about 40% to about 70% preferably from about 45% to about 65%, for example 50%, by weight of the composition.

The tensile strength of the sample of starch can be measured in any suitable test. Examples of test procedures are described in Hiestand & Smith (1984), Powder Technology, 38, 145-159, and Hiestand & Smith (1991), International Journal of Pharmaceutics, 67, 231-246, and these articles are included in this description as a reference.

Testing tensile strength, which can be used (hereinafter in this description is called "test triaxial tensile strength"), you want to get the number of briquettes sample of starch with subsequent determination of the tensile strength of briquettes using automated multifunctional tester for tablets (MTT). The briquettes prepared with the compressive effort of the different degrees to obtain briquettes with an interval of a proportion of solids. Because of the composition of the tablets with delayed release typically have a share solids about 0.8, it is useful to obtain briquettes approaching such proportion of solids.

The absolute density of the sample of starch can be measured using galiwango pycnometer.

To obtain briquettes using triaxial tablet press with software control. The output voltage of the punch and torque sensors matrix tablet press is first set to zero. The punch and the grease matrix p is the Roshko of stearate and the matrix is placed in a press. Choose on your computer settings compression and decompression. Weigh the need for briquetting amount of starch and loaded into the cavity of the matrix. The resulting layer of powder is leveled with a spatula. Insert the plug into the matrix and begin computer-controlled cycle of compression/decompression.

Just before the end of the compression phase register thickness of the briquette, as measured by LVDT. At the end of the compression phase register of the final compressive force, the measured voltage on the torque sensor plug.

At the end of the decompression phase divert the plungers of the punch and matrix. The briquette is removed from the matrix and check for defects such as cracking and adhesion. Cracking can be reduced by increasing the time of decompression. If the brick has no defects, measure its length, width, thickness and weight, in order to calculate the apparent density. The proportion of solids is calculated by dividing the absolute density on apparent density.

Upon receipt MTT to determine the tensile strength is maintained for a suitable program. To a torque sensor MTT screw plate and a device for determining the tensile strength vidvigayt MTT opposite plate. The signal from the torque sensor are controlled by the computer and adjust the zero offset on the driver signal d is I provide a positive reference voltage, as close as possible to zero. Choose a speed that will give a time constant of approximately 15 seconds (typically, the selected speed will be equal to from about 0.8 to about 1.2 mm·-1.

Feel briquette is placed in a holder device for determining the tensile strength. Include the motor through the computer, pushing the plate to the brick until then, until you find the surface of the briquette, and stop plate a few millimeters from the briquette. Include oscilloscope for recording the force applied to the briquette, and again start the motor. Plate vidvigayt in the briquette to detect cracking or mind, or the sound and the motor immediately switch to reverse.

Record the peak force on oscillogram. Tensile strength is calculated from the peak force using appropriate computer programs.

Build a schedule according to several experiments using briquettes in the range of fractions of solids near 0.8 and evaluate the tensile strength percentage solids of 0.8. If the tensile strength percentage solids of 0.8 is equal to approximately 0.15 kN·cm-2or a larger value, the sample of starch is considered suitable for use in preparation of the composition according to the invention.

Now unexpectedly discovered that a much more simple the first test, which can be done in a production environment can be used to evaluate the tensile strength of the sample of starch, in particular to determine whether the sample of starch tensile strength of at least about 0.15 kN·cm-2with a share of solids, characteristic for the desired tablet delayed release.

According to this test briquettes starch is obtained on a standard tablet press machine in the range of compressive forces. For example, it is found that satisfactory results are obtained Carver press (for example, the model 3888.1DT0000)with snap flat surface of suitable diameter (e.g., 10/32 of an inch or approximately 0.7 cm for briquette 300 mg), working under a compressive effort from about 4 to about 16 kN (from about 900 to about 3600 f/d2for the dwell time in the mold under a pressure of at least about 4 seconds. For example, such briquettes can be obtained with 1000, 1500, 2000 and 3000 f/d2(4,45, 6,67, 8,90 and 13,34 kN). Preferably, use the dwell time in the mold under a pressure of at least about 10 seconds, preferably at least about 30 seconds, more preferably at least about 60 seconds. For clarification, it is found that satisfactory results are obtained when the exposure time in the mold 90 seconds. The weight, diameter and t is Lino each briquette measure accurately (on the other hand, the diameter can be estimated as equal to the diameter of the snap), to be able to calculate the apparent density and, consequently, the proportion of solid matter, and the absolute density is measured as described above, for example, using galiwango pycnometer.

Then determine the hardness of each of the pellets thus obtained, in any suitable test for the hardness of the tablets, for example, by using a Durometer Key HT 500. Hardness is a measure of the effort required to cause crushing of the briquette, and typically is expressed in units such as kilopond (CP) (kiloponds, kp) or units of strong-Cobb (Strong-Cobb) (SCU). Hardness of approximately 10.2 p, or approximately 14.4V SCU conforms to the effort of 0.1 kN.

For the purposes of the present invention is that the crushing strength of the briquette is equivalent to the tensile strength. Thus, the tensile strength (sT, kN) can be calculated from the equation

sT= 2F/pDH,

where F represents the force required to cause crushing (in kN), D represents a diameter of briquette (in cm), and H is the thickness of the briquette (in cm). For example, briquettes with a diameter of 0.7 cm and thickness 0.4 cm, has a hardness of 20 SCU (equivalent to the force 0,139 kN)has a calculated tensile strength 0,316 kN·cm-2.

Then for the sample of starch estimate the ratio of the giving of the tensile strength and the fraction of solids. This can be done by plotting the data for the tensile strength and the fraction of solids in the graph (the proportion of solids tends to increase with increasing compressive efforts in obtaining briquettes) or by regression analysis. From this ratio, we can estimate the tensile strength at a standardized value of the share of solids. Selected standardized value is a value that represents the percentage of solids need tablets with delayed release, for example, 0.8.

Found that, when the substance of the briquette is a pre-gelatinizing starch, tensile strength, determined in a simple test, just described above, unexpectedly approaches to measuring the "true" tensile strength, carried out triaxial test method for tensile strength, described previously, which in turn essentially similar methods known in the art, such as the method described Hiestand & Smith (1984), CIT. above.

Also found that the longer the dwell time under pressure into the mold (e.g., 90 seconds) the test method of the present invention gives the best correlation with the triaxial tensile strength than a very short time (for example, 4 seconds). See below the example 1 and Fig. 1 and 2.

So about what atom, according to one embodiment of the invention it relates to a method of determining the suitability of starch for use in deliver oral tablet delayed release containing an active pharmaceutical agent having solubility not less than about 10 mg/ml, dispersed in the matrix containing a hydrophilic polymer and a starch. The method includes the stage

(a) obtaining briquettes sample of starch in tablet press machine in the interval compressive effort applied over time under pressure in the mold at least about 4 seconds;

(b) measuring the hardness of each briquette, expressed as the force required to cause crushing of the briquette;

(C) determine the percentage of solids of each briquette;

(d) calculate the tensile strength sTeach briquette from the equation

sT= 2F/pDH,

where F represents the force required to cause crushing, D represents the diameter of the briquette, and H is the thickness of the briquette;

(e) establishing a ratio of the tensile strength and the fraction of solid briquettes, for example, by plotting these parameters and/or by implementing a regression analysis; and

(f) assessment ratio set at stage (e), tensile strength at to the e solids, characteristic for the desired tablet delayed release; for example, with a share of solids 0,8.

If the tensile strength of the starch is such that for a given estimate is at least approximately 0.15 kN·cm-2starch is considered suitable for use.

Especially preferred starch has a tensile strength of at least about 0,175 kN·cm-2, even more preferably at least approximately 0.2 kN·cm-2when the proportion of solid matter, which is characteristic for the desired tablet delayed release.

Even among the commercially available pre-gelatinizing starch is the preferred type of starch for use in the compositions of the invention, there are substantial variations in tensile strength. Pre gelatinisation starches that do not meet the criteria established in this description, it is difficult to identify without testing, for example, by the method described above. Such pre-gelatinisation starches generally not suitable for commercial production of the composition of matrix tablets with delayed release of water-soluble drugs or prodrugs because of the problems listed directly below.

Tablet without coating or the core of the tablet prior to coating containing Rahman and hydrophilic polymer, acting as a matrix for water-soluble drugs or prodrugs, must have a certain minimum hardness in order to be able to resist damage and/or abrasion due to the mechanical stresses that occur during high-speed tabletting operations (including all stages and including a location of the tablets in the tank). The minimum acceptable hardness will depend on a number of factors, including the magnitude of the mechanical stresses, but is typically at least about 20 SCU, preferably at least about 22 SCU, preferably at least about 24 SCU (about 17 KP).

The hardness can be increased by increasing the compressive force applied tablet press, but only to a certain level. At least in the case of tablets described in this description, above a certain compressive efforts to further increase the compressive effort gives a small increase in hardness of the tablets or not give it at all. In other words, there is a maximum hardness achieved by the compression of a specific composition, the starch/hydrophilic polymer/active substance. Starch, for maximum hardness, inadequate to withstand the mechanical stresses of high-speed tabletting operations, are not suitable for the purposes of the Britania. As can be seen in Fig. 3, I found that some pre-gelatinisation starches provide maximum hardness 20 SCU or less; now they are identified as starches with low tensile strength (0,1 kN·cm-2or less according to the test method according to the invention using the exposure time under pressure of 90 seconds).

Even if you reach the maximum hardness of at least about 20 SCU, with starch with a low tensile strength, it can only be achieved with extremely high compressive forces. The need for such efforts reduces the speed and efficiency and increases the cost of operation tabletting and for these reasons is undesirable.

When the tablets should be by way of additional stage after compression, in particular the stage of coating, the mechanical strength increases significantly. According to a preferred embodiment of the tablet delayed release according to the invention also contains floor.

In the case of drugs and prodrugs with high solubility in water, referred to in this description, the hydrophilic polymer matrix is often inadequate to provide sustained release over a long enough period to be able a single injection in the ducks. It is assumed that such medicines can easily leach from hydrophilic matrix upon contact with an aqueous medium, such as gastrointestinal fluid. It is therefore desirable to slow the release of drug through the creation of a whole tablet coating governing the release. This coating typically contains a hydrophobic or water-insoluble polymer component, such as ethylcellulose, together with a hydrophilic or water-soluble pore-forming component, such as a receiver array.

Found that, when the use of starch with a tensile strength of at least approximately 0.15 kN·cm-2preferably at least about 0,175 kN·cm-2preferably at least approximately 0.2 kN·cm-2when the proportion solids typical for tablets (for example, from about 0.75 to about 0,85), the composition is particularly suitable for high speed operation tabletting, which includes a step of applying a tablet layer regulating the release.

Alternatives ethylcellulose and a receiver array as components of the coating governing the release, include other cellulose (for example, methylcellulose, hydroxypropylcellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, esters of cellulose, such as cellulose acetate, etc., the polyvinyl acetate, polyvinylpyrrolidone, polymers and copolymers of acrylic acid and methacrylic acid and their esters, polyethylene glycol, carrageen and other gums and similar substances.

The layer regulating the release, if present, is typically from about 1% to about 15%, preferably from about 2.5% to about 10%, by weight of the whole tablet in General. Hydrophobic or water-insoluble component, preferably comprising ethylcellulose, typically ranges from about 1% to about 10%, preferably from about 2% to about 7%, by weight of the whole tablet in General. A pore-forming component, preferably comprising a receiver array, typically present in an amount of from about 5% to about 50%, preferably from about 10% to about 40%, by weight of water-insoluble or hydrophobic component.

The coating, if present, may contain, optionally, other pharmaceutically acceptable excipients, such as plasticizers, dyes, etc.

For clarification, the layer regulating the release, in the amount of from about 2.5% to about 5% by weight of the core tablet (i.e. the mass of the tablet except for the cover) contains material based on ethyl cellulose (e.g., Surelease®, use) and a pore-forming material on the basis of the receiver array (e.g., Opadry®, use) in a mass ratio of from primer is 3:1 to about 4:1.

The layer or coating, which regulates the release is necessary to apply a uniform thickness as possible, for optimal speed control of release of the active pharmaceutical agent.

On the other hand, or in addition, the tablet delayed release according to the invention contains a non-functional coating. Non-functional coating may contain a polymer component, such as a receiver array, optionally, with other ingredients, for example one or more plasticizers, dyes, etc. the Term "non-functional" in this context means no significant influence on the properties of tablets to release the drug and does not imply that the coating serves no purpose utility. For example, such a coating can give a characteristic appearance to the tablet, to provide protection against abrasion during packaging and transport, to facilitate swallowing and/or have other favorable properties. Non-functional coating should be applied in sufficient quantity to ensure complete coverage of the tablets. Typically, suitable is a number from about 1% to about 10%, a typical amount of from about 2.5% to about 5%, by weight of the whole tablet as a whole.

Tablets without coating or core tablets with a coating according to the invention, in addition to comp the components of starch and hydrophilic polymer, described above, optionally, contain one or more pharmaceutically acceptable excipients. Such excipients include, without limitation, glidant and lubricants. It may also include other conventional excipients known in the technique.

Glidant can be used to improve flow characteristics of the powder before and during tabletting and to reduce caking. Suitable galantai are colloidal silicon dioxide, magnesium trisilicate, powdered cellulose, starch, talc, rejonowy calcium phosphate and similar substances. In one embodiment as glidants include colloidal silicon dioxide in an amount up to about 2%, preferably from about 0.2% to about 0.6%, by weight of the tablet.

The lubricating substance can be used to facilitate release of the tablet from the device in which it is received, for example, by preventing adhesion to the surface of the upper punch ("otseivaniya") or lower punch ("bonding"). Suitable lubricants include magnesium stearate, calcium stearate, canola oil, glycerylmonostearate, gidrirovannoe vegetable oil, magnesium oxide, mineral oil, prosumer, polyethylene glycol, polyvinyl alcohol, sodium benzoate, sodium lauryl sulfate, sodium fumarate, stearic acid, talc, art is Arat zinc and similar substances. In one embodiment as the lubricant include magnesium stearate in an amount of from about 0.1% to about 1.5%, preferably from about 0.3% to about 1%, by weight of the tablet.

The pill can have any suitable size and shape, for example round, oval, polyhedron or pads, and, optionally deposited on the surface of the non-functional labels. Especially in the case of tablets, coated them, preferably, create swallowed whole and therefore typically not provided with a notch for breaking. Tablets according to the invention can be packaged in containers accompanied liner that provides relevant information for the patient, such as, for example, information about the dosage and administration, contraindications, precautions, and interactions with medicines and harmful reactions.

The invention also relates to a method of treatment of a subject having a condition or disorder, in which is shown an active pharmaceutical agent having solubility not less than about 10 mg/ml, comprising oral administration to a subject the pharmaceutical composition with delayed release in the form of tablets containing agent, dispersed in the matrix containing a hydrophilic polymer and a starch having a tensile strength of at least approximately 0.15 kN·cm-2when the OLE solids, typical tablets. Preferably, the composition is administered no more than once per day.

In one embodiment, the condition or disorder is a condition or disorder of the Central nervous system, and the tool is the Central nervous system, the definition of which is given in this description. State and Central nervous system disorders include conditions and disorders with neurological and/or psychiatric component.

For clarification, the conditions and disorders of the Central nervous system, which can be treated by the method of the invention, include, for example, personality disorders, including paranoid, schizoid, schizoid type, bipolar, scenic, delusional, narcissistically, emotional instability, psychopathic and sociopathically personality disorders; disorders due to habits and impulse control disorders including pathological gambling, stealing, trichotillomania etc.; obsessive-compulsive disorder; passive-aggressive disorder; acute and transient psychotic disorder; psychotic depression; schizoaffective disorder; hypochondria; cyclothymia; dysthymia; manic depression; major depressive disorder; depression treatment resistance; initial schizophrenia in adults and children; drug dependency, including malicious application is their abuse, addiction and dependence on opioids, narcotics, barbiturates, alcohol, benzodiazepines, amphetamines, cocaine, cannabinoids, hallucinogens, stimulants, nicotine (tobacco) and solvents; the withdrawal state and mood disorders and psychotic disorders such addiction; sexual dysfunction, including Hypo-functional disorder of sexual desire, sexual aversion and avoidance and erectile dysfunction; disorders of sexual identity; disorders of sexual preference; generalized anxiety disorder; social anxiety disorder; mixed anxiety and depressive disorder; attention deficit disorder - hyperactivity disorder (ADHD) and depression and anxiety associated with this; depression, anxiety, emotional rosregulirovanie and behavior disorders associated with mental retardation; developmental disorders, including autism, syndrome Aspargine and rett syndrome; conductive disorders, and disorders of attachment in children; premenstrual dysphoric disorder; postpartum depression; phobias, including social phobia, acrophobia and specific phobias, such as those associated with hospitals, injections, Venezuela etc.; posttraumatic stress disorder; dissociative disorders; syndrome the Brik; affective the Sam the STS, including depression, bipolar disorder and recurrent depressive disorder, organic mood disorders, anxiety and emotional instability, as a result, for example, brain damage or dysfunction resulting from head trauma, intracranial masses, shock, etc.; chronic fatigue; stress-induced psychotic episodes; dementia, including presenilny dementia, the disease Peak, vascular dementia, dementia multi-infarct, Alzheimer's disease, dementia associated with the disease of Creutzfeldt-Jakob disease, and dementia associated with HIV; other neurodegenerative disorders, including disease Parkinson's and Huntington's disease; suicidal behavior; appetite disorders, including anorexia, bulimia and disorder of appetite due to drinking; adjustable disorders; somatized disorder; somatoform autonomic dysfunction; somatoform pain disorder; panic attack; panic disorder; amnesia; neuropathic pain; fibromyalgia; migraine; epilepsy; tinnitus; enuresis; sleep disorders, including insomnia, hypersomnia, narcolepsy, nightmares and night terrors; delirium; the totality of symptoms after concussion; multiple sclerosis; tremors; muscle spasms; syndrome of the mouth of the smaller legs; the syndrome of Lennox; motor and vocal TIC; disease Tourette's; supranuclear palsy; syndrome Shay-Drager; trigeminal neuralgia; bell's palsy; disease of motor neurons, such as the side amyotrophy sclerosis; and psychosomatic and psychological conditions associated with diseases of the CNS, such as diabetes, inflammatory disease, infertility, allergies, psoriasis, asthma, hypertension, hyperactive bladder, thyroid disorders, obesity, immune disorders and malignant tumors.

In a specific embodiment, the condition or disorder is a condition or disorder that responds to treatment with agonists dopamine receptor D2or SNRI therapy, and active pharmaceutical agent is an agonist at the dopamine receptor D2or SNRI or their prodrugs.

Currently, the preferred agonists dopamine receptor D2for use according to the method of the invention are salts of pramipexole or sumanirole. Such agonists dopamine receptor D2especially suitable for the treatment of Parkinson's disease. In the currently preferred SNRI for use according to the method of the invention are salts of reboxetine and (S,S)-reboxetine. Such SNRI particularly suitable in the treatment of depressive illness and neuropathic pain, including h the following herpetic neuralgia and diabetic neuropathy.

For clarification, in the case of sumanirole suitable daily dosages include 0,5, 1, 2, 4, 8, 12 and 24 mg sumanirole in the form of the maleate of sumanirole. In the case of pramipexole suitable daily dosages include 0,375, 0,5, 0,75, 1,0, 1,5, 3,0 and 4.5 mg of the monohydrate of pramipexole dihydrochloride. In the case of reboxetine or (S,S)-reboxetine suitable daily dosages include 1, 2, 4, 6, 8, and 12 mg of reboxetine in the form of its salts or nelfinavir (S,S)-reboxetine in the form of its succinate salt.

In another embodiment the composition according to the invention is administered in combination therapy with one or more other drugs or prodrugs. The term "combination therapy" in this case refers to the treatment regimen, where the tool provided by the composition according to the invention and the other agent is administered separately or together, sequentially or simultaneously, in a way that gives a beneficial effect from the co-introduction of these therapeutic agents. This beneficial effect may be related to the pharmacokinetics or pharmacodynamics of the joint introduction of therapeutic agents and other parameters. Combination therapy may, for example, be allowed to enter a lower dose of one or both of the funds than the doses that you would typically enter when alone, and that reduces the risk of harmful actions, connected the CSOs with higher doses. On the other hand, combination therapy may lead to increased therapeutic effect during normal dose of each tool when used alone. In this case, does not mean that "combination therapy" embraces the introduction of two or more therapeutic agents as part of separate schemes monotherapy, which accidentally and randomly appear in a sequential or concurrent treatment.

The composition of the invention may be particularly suitable for combination therapy, in particular, when the second tool is a tool that is administered or which you can enter once per day. There are significant advantages in convenience for the patient and his / her consent, when both components of combination therapy can be administered simultaneously and with the same frequency. This is especially true when patients are elderly people or people suffering from memory impairment.

With the simultaneous introduction of both a component of combination therapy can be entered in separate dosage forms or in the General composition, i.e. in a single dosage form. The sequential introduction of or in separate dosage forms the second tool you can enter any suitable way and in any pharmaceutically acceptable dosage form, for example, in the manner and/or in the dosage form, the data than for the composition of the invention. In the preferred embodiment both components of combination therapy include part of a single dosage form.

An example of combination therapy includes the introduction of once per day the composition of the invention containing SNRI, such as salt reboxetine or (S,S)-reboxetine, and the introduction of once per day an SSRI, such as fluoxetine, fluvoxamine, paroxetine or sertraline or their salts. Combination therapy with SNRI/SSRI features, for example, for the treatment of depression treatment resistance as disclosed in Forbes & Rogers (2003), Progress in Neurology and Psychiatry, 7(2), 10-14; according to the present invention the two components of this combination therapy, you can enter once a day, in which patients agree more willingly.

EXAMPLES

Example 1

Determine the tensile strength of the six obtained commercially parties pre gelatinizing starch using triaxial test procedure for tensile strength described in the description above. The results for tensile strength in proportion of solids to 0.8 are given in table. 1.

Table 1

The tensile strength of the parties pre-gelatinizing starch with a share of solids 0,8 (triaxial test procedure)
PartyTensile strength (kN·cm-2)
10,323
20,220
30,074
40,119
50,287
60,236

There is a big difference in tensile strength pre-gelatinizing starches, ranging from 0,074 to 0,323 kN·cm-2. Batch 3 and 4, showing the lowest values of tensile strength were from the same manufacturer. Party 1, 5 and 6, showing the highest values of tensile strength were from another manufacturer. Part 2, showing an intermediate value of tensile strength was from a third manufacturer.

Example 2

Determine the tensile strength of six parties pre gelatinizing starch by using this simplified test procedure.

Briquettes starch each party will receive in the press Caver, model 3888.1DT0000 with snap flat surface 10/32 inch (0.7 cm), when the compressive efforts, 1000, 1500, 2000 and 3000 f/d2(4,45, 6,67, 8,90 and 13,34 kN) for holding under daveiam 4 seconds and 90 seconds. Get the briquettes from three parties pre gelatinizing starch (lots 7, 8 and 9) from the same manufacturer as parties and 4, using the exposure time under the pressure of only 90 seconds. Measure the mass and thickness of each brick (with diameter equal to the diameter of the snap), to be able to calculate the apparent density. The absolute density of each batch of starch was measured using galiwango pycnometer. The proportion of solids is calculated as the ratio of the apparent density to the absolute density.

Hardness (force required for crushing of the sample) of each pellet was determined by using a Durometer Key HT 500. Tensile strength is calculated from the obtained force and size of briquette using equation

sT= 2F/pDH,

above.

Perform regression analysis to determine the ratio of the tensile strength and the fraction of solids for each batch of starch and calculate the tensile strength of the standardized proportion of solids to 0.8. Data are given in table. 2.

Table 2

The tensile strength of the parties pre-gelatinizing starch with a share of solids 0,8 (simplified test procedure according to the invention)
PartyTensile strength (kN·cm-2)
The exposure time 4 The exposure time 90
10,3100,306
20,2270,191
30,0920,085
40,1340,096
50,3160,277
6of 0.3330,242
7not ODA.0,087
8not ODA.0,088
9not ODA.0,172

Correlation of tensile strength, measured in a simplified test using the exposure time under the pressure of 4 seconds (this example) with a tensile strength, measured in the triaxial test procedure of example 1, shown graphically in Fig. 1.

Correlation of tensile strength, measured in a simplified test using the exposure time under pressure of 90 seconds (this example) with a tensile strength, measured in the triaxial test procedure of example 1, shown graphically in Fig. 2.

Good correlation is found for both exposure times under pressure, but the correlation is particularly close when in a simplified test using the dwell time under pressure for 90 seconds. From this it follows that simplified the test described herein, and can the be used to evaluate the tensile strength of the party of starch for the purpose of prediction, whether the party starch to obtain a composition for tablets with delayed release of the present invention.

Example 3

Get tablets delayed release maleate of sumanirole having the compositions listed in table. 3. The content of the active substance in mg expressed as the content of sumanirole Foundation.

Table 3

Composition for tablets maleate of sumanirole example 3
The content of the active substance (mg)
Ingredient0,5124881224
Amount (wt.%)
Maleate of sumanirole0,230,450,91,83,63,6of 5.410,9
A receiver array, type 2208,

4000 mPa.s
35,0035,0035,035,035,035,035,035,0
Pre gelatinizing starch63,8763,6563,262,3of 60.560,052,5
Colloidal silicon dioxide0,400,400,40,40,40,40,40,4
Magnesium stearate0,500,500,50,50,51,01,01,0

All the ingredients except the lubricant (magnesium stearate), sifted to remove lumps and mixed by a mixer with low shear effort at 24 rpm for 10-30 minutes. Then into the mixer sift lubricating substance and the materials mixed for 2-5 minutes. The mixture with the lubricant is pressed into tablets in the form of pads using teletrauma machine Kilian S100.

Example 4

Get a tablet, like the tablets of example 3, using pre gelatinizing starch parties 1-6, tested in examples 1 and 2. Determine the maximum hardness of the tablets, which you can obtain from each party pre gelatinizing starch.

Perform correlation maximum hardness and tensile strength used party starch, measured in a simplified test of example 2 using the exposure time under pressure for 90 seconds. Results n the cauldrons in Fig. 3. The correlation is essentially linear.

In subsequent tests of tablets with different hardness are used as cores for coating and experiencing resistance to erosion during high speed operation of the coating. Find that core tablets with a hardness of at least about 24 SCU (about 17 CP) have acceptable resistance to erosion. As can be seen in Fig. 3, such a degree of hardness can be achieved by using a pre-gelatinizing starch having a tensile strength of at least about 0,175 kN·cm-2. Pre gelatinizing starch parties 3 and 4 is unsuitable, having a tensile strength of less than approximately 0.15 kN·cm-2and tablets with the same starch have a maximum hardness of not more than about 20 SCU (about 14 KP).

Example 5

Get tablets delayed release monohydrate pramipexole dihydrochloride having the compositions listed in table. 4.

Table 4

Composition of tablets pramipexole dihydrochloride of example 5
IngredientAmount (mg)
Monohydrate pramipexole dihydrochloride0,3750,751,5 3,04,50,3750,3754,5
A receiver array, type 2208,

4000 MPa·
140,0140,0140,0140,0140,070,0157,5157,5
Pre gelatinizing starch206,5206,1205,4the amount of 203.9202,4of 101.5189,0184,9
Colloidal dioxide

Silicon
1,41,41,41,41,41,41,41,4
Magnesium stearate1,751,751,751,751,751,751,751,75
Only350350350350350175350350

Tablets get the procedure described in example 3, using pre gelatinizing starch having a tensile strength of at least about 0,175 kN·cm-2.

Example 6

Get coated tablets, sustained-release pramipexole dihydrochloride having the composition specified in the table. 5.

Table 5

Composition of coated tablets of example 6
IngredientAmount (mg)
Monohydrate pramipexole dihydrochloride0,375
A receiver array, type 2208, 4000 MPa·140,0
Pre gelatinizing starch206,5
Colloidal silicon dioxide1,4
Magnesium stearate1,75
Core350
The coating material on the basis of

ethyl cellulose (Surelease®)
7,88
The coating material on the basis of

A receiver array (Opadry®)
2,63
Floor, total10,5

Get core tablets in the same way as in example 5, using pre-gelatinizing starch having a tensile strength of at least about 0,175 kN·cm-2. The solution for coating was prepared as follows. The material on the basis of the receiver array Opadry® number 6,004 g add to 106,682 g of water and stirred for 45 minutes to obtain a mixture of a receiver array. Then to the mixture add a receiver array 72,045 g of material based on ethyl cellulose Surelease® and stirred for 30 minutes to obtain a solution for pokr is an event.

The solution for the coating applied to the core tablets using a bath for coating 12-inch (30 cm) Vector LCDS or 24-inch (about 60 cm) Thomas Accla-Coata for about 15 minutes at a temperature of at least about 70°C. After curing temperature reduce for about 8 minutes until the temperature of the release of approximately 45aboutC.

Example 7

Get coated tablets, sustained-release pramipexole dihydrochloride having the composition specified in the table. 6.

Table 6

Composition of coated tablets of example 7
IngredientAmount (mg)
Monohydrate pramipexole dihydrochloride0,375
A receiver array, type 2208, 4000 mPa.s140,0
Pre gelatinizing starch206,5
Colloidal silicon dioxide1,4
Magnesium stearate1,75
Core350
The coating material on the basis of

ethyl cellulose (Surelease®)
8,4
The coating material on the basis of

A receiver array (Opadry®)
2,1
Floor, total 10,5

Get core tablets exactly as in example 5, using pre gelatinizing starch having a tensile strength of at least about 0,175 kN·cm-2. The solution for coating was prepared as follows. The material on the basis of the receiver array Opadry® number 4,801 g add to 103,041 g of water and stirred for 45 minutes to obtain a mixture of a receiver array. Then to the mixture add a receiver array 76,819 g of material based on ethyl cellulose Surelease® and stirred for 30 minutes to obtain a solution for coating.

Coating to increase the weight to 3 wt.% and curing the coated tablets perform exactly the same as in example 6.

Example 8

Get coated tablets, sustained-release pramipexole dihydrochloride having the composition specified in the table. 7.

Table 7

Composition of coated tablets of example 8
IngredientAmount (mg)
Monohydrate pramipexole dihydrochloride0,375
A receiver array, type 2208, 4000 MPa·140,0
Pre gelatinizing starch206,5
Colloidal silicon dioxideMagnesium stearate1,75
Core350
The coating material on the basis of

ethyl cellulose (Surelease®)
13,13
The coating material on the basis of

A receiver array (Opadry®)
of 4.38
Floor, totalof 17.5

Get core tablets exactly as in example 5, using pre gelatinizing starch having a tensile strength of at least about 0,175 kN·cm-2. The solution for coating was prepared as follows. The material on the basis of the receiver array Opadry® number 10,003 g add to 177,737 g of water and stirred for 45 minutes to obtain a mixture of a receiver array. Then to the mixture add a receiver array 120,03 g of material based on ethyl cellulose Surelease® and stirred for 30 minutes to obtain a solution for coating.

Applying a coating to increase the total mass of 3 wt.% and curing the coated tablets perform exactly the same as in example 6. After this first stage of curing, the coating is applied again and end up creating a tablet with increasing mass to about 5%, followed by curing for about 15 minutes at a temperature of at least about 70aboutC. After the curing temperature of the Roux reduce for about 8 minutes until the temperature of the release of about 45° C.

Example 9

Get coated tablets, sustained-release pramipexole dihydrochloride having the composition specified in the table. 8.

Table 8

Composition of coated tablets of example 9
IngredientAmount (mg)
Monohydrate pramipexole dihydrochloride0,375
A receiver array, type 2208, 4000 MPa·140,0
Pre gelatinizing starch206,5
Colloidal silicon dioxide1,4
Magnesium stearate1,75
Core350
The coating material on the basis of

ethyl cellulose (Surelease®)
14,0
The coating material on the basis of

A receiver array (Opadry®)
3,5
Floor, totalof 17.5

Get core tablets exactly as in example 5, using pre gelatinizing starch having a tensile strength of at least about 0,175 kN·cm-2. The solution for coating was prepared as follows. The material on the basis of the receiver array Opadry® count 8,002 g add to 171,735 g of water and peremeshivayte for 45 minutes to obtain a mixture of a receiver array. Then to the mixture add a receiver array 128,032 g of material based on ethyl cellulose Surelease® and stirred for 30 minutes to obtain a solution for coating.

Coating to increase the total mass of 5 wt.% and curing the coated tablets perform exactly the same as in example 8.

Example 10

The dissolution profiles of tablets containing 0.375 mg pramipexole dihydrochloride each of examples 5, 6 and 9 evaluate the standard analysis of in vitro dissolution, USP, in the following conditions. Use the device 1 USP for mixing solvent medium (900 ml of 0.05 M phosphate buffer at pH 6.8) at a spin speed of 100 rpm and a temperature of 37°C.

Data are presented in Fig. 4. Tablet without coating of example 5 and the tablet of example 6 with a 3% coating containing 25% of a pore-forming, show very similar overall profile of dissolution. However, on closer inspection it will be seen that the uncoated tablet of example 5 shows a more rapid initial dissolution, so after 1 hour and 2 hours processing of samples percentage of the solute is higher than in the case of coated tablets of example 6. For example, for 1 hour tablet with the coating of example 6 shows the dissolution of only 11%, while the uncoated tablet of example 5 shows the dissolution of 15%. Similarly, for 2 hours tablet with the coating of example 6 which shows the dissolution of not more than 20%, while tablet without coating of example 5 shows the dissolution of 24%.

Dissolving tablets of example 9 with 5% coverage, containing 20% of the pore-forming, shows the dissolution profile is slower than the tablet of example 5 or tablet of example 6.

Example 11

Get tablets with delayed release of succinate (S,S)-reboxetine, having the compositions indicated in table. It should be noted that each tablet contains 5.5 mg succinate (S,S)-reboxetine, equivalent to 4 mg of (S,S)-reboxetine Foundation.

Table 9

Composition of tablets with succinate (S,S)-reboxetine example 11
IngredientAmount (mg)
Succinate (S,S)-reboxetine5,55,55,5
A receiver array, type 2208, 4000 MPa·40,080,0160,0
Pre gelatinizing starch53,5112,5of 230.5
Colloidal silicon dioxide0,51,02,0
Magnesium stearate0,51,02,0
Only100,0200,0400,0

Tab is EDI receive procedure described in example 3, using pre gelatinizing starch having a tensile strength of at least about 0,175 kN·cm-2.

Example 12

Evaluate the dissolution profiles of the tablets of example 11 with 4 mg succinate (S,S)-reboxetine example 11 in the standard analysis of in vitro dissolution, USP, in the following conditions. Use the device 2 USP for mixing solvent medium (1 l of 0.05 M phosphate buffer at pH 6.8) at a speed of rotation of the blades 50 rpm and a temperature of 37°C. Then the medium is filtered and the samples analyzed by means of UV-detection.

Data are presented in Fig. 5. The tablet having a total weight of 100 mg, is dissolved faster than others, and tablet weight of 400 mg dissolved slowest. The total tablet weight of 200 mg has an average dissolution rate.

1. Pharmaceutical composition with delayed release in the form of tablets that are delivered orally, contains an active pharmaceutical agent selected from (S,S)-reboxetine or its salts and pramipexole or salts thereof, active pharmaceutical agent is from about 0.01 wt.% approximately 25 wt.% composition and dispersed in the matrix containing a hydrophilic polymer and a starch having a tensile strength of at least about 0.15 kN·cm-2at least approximately 0,175 kN·with the -2or at least about 0.2 kN·cm-2when the share of solids, typical tablets, where the hydrophilic polymer is from about 20 wt.% approximately 70 wt.% composition, and the starch is from about 25 wt.% approximately 75 wt.% song.

2. The composition according to claim 1, where the starch is a pre-gelatinizing starch.

3. The composition according to claim 1, where the starch is present in an amount from about 40 wt.% approximately 70 wt.% or from about 45 wt.% approximately 65 wt.%.

4. The composition according to claim 1, where the hydrophilic polymer is selected from the group consisting of methylcellulose, hydroxypropylmethylcellulose, nutricology and Carbonara.

5. The composition according to claim 1, where the hydrophilic polymer is a hypromellose.

6. The composition according to claim 1, where the hydrophilic polymer is present in amount from about 30 wt.% to about 60 wt.% or from about 35 wt.% approximately 50 wt.%.

7. The composition according to claim 1, where the active pharmaceutical agent is a succinate (S,S)-reboxetine.

8. The composition according to claim 7, containing approximately 0.2 to approximately 15 mg of reboxetine on the tablet, or from about 1 to about 12 mg of reboxetine on the pill.

9. The composition according to p., optionally containing coating on the tablet.

10. The composition according to claim 9, where the said coating is a layer of regulating the release.

11. The composition of claim 10, where the layer regulating the release ranged from approximately 1% to approximately 15% by weight of the tablet.

12. The composition according to claim 9, where the said coating is non-functional coating.

13. Pharmaceutical composition in the form of tablets that are delivered orally, containing succinate (S,S)-reboxetine in the amount of from about 0.2 mg to about 15 mg per tablet, or from about 0.1 to 10 wt.% the composition, dispersed in the matrix containing (a) a receiver array in amount from about 35% to about 50% by weight of the tablet and (b) pre-gelatinizing starch having a tensile strength of at least about 0.15 kN·cm-2with a share of solids to 0.8, in the amount of from approximately 45% to approximately 65% by weight of the tablet.

14. The method of determining the suitability of starch for use in tablet delayed release, delivered orally, contains an active pharmaceutical agent having solubility not less than about 10 mg/ml, providing for stage

(a) obtaining briquettes sample of starch in tablet press machine in the range is imusic efforts applied over time under pressure in the mold at least about 4;

(b) measuring the hardness of each briquette, expressed as the force required to cause crushing of the briquette;

(c) determine the percentage of solids of each briquette;

(d) calculate the tensile strength σTeach briquette from the equation

σT=2F/πDH

where F represents the force required to cause crushing, D represents the diameter of the briquette, and H is the thickness of the briquette;

(e) establishing a ratio of the tensile strength and the fraction of solid briquettes; and

(f) using the formulas for estimation of tensile strength with a share of solids, characteristic for the desired tablet delayed release;

moreover, the starch is considered suitable for the specified use, if its tensile strength, it is estimated, therefore, equal to at least approximately 0.15 kN·cm-2.

15. The composition according to claim 1, where the active pharmaceutical agent is a pramipexol or its salt.

16. The composition according to claim 1, where the active pharmaceutical agent is an S-enantiomer of pramipexole or its salt.

17. The composition according to claim 1, where the active farmaceuticas the second agent is a monohydrate of pramipexole dihydrochloride.

18. Composition according to any one of p-17, where the active pharmaceutical agent is about 0.05 wt.% approximately 5 wt.% song.

19. Composition according to any one of p-17, where the composition comprises approximately 0.1 to approximately 10 mg of the active pharmaceutical ingredient in the pill, approximately 0.2 to approximately 6 mg of the active pharmaceutical ingredient in the pill or from about 0.3 mg to about 5 mg of the active pharmaceutical ingredient in the pill.

20. The use of the pharmaceutical composition according to any one of claims 1 to 13 and 15-19 for the treatment of disorders or conditions selected from depressive psychosis, neuropathic pain and Parkinson's disease.

21. The application of claim 20, where the pharmaceutical composition is applied no more than once a day.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes a novel compound 4-(2-butylamino)-2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl)[1,5-a]-1,3,5-triazine of the formula (I):

, its steroisomeric forms or pharmaceutically acceptable salts, pharmaceutical composition comprising thereof and its using for preparing pharmaceutical composition used in treatment of anxiety in mammals.

EFFECT: valuable medicinal property of compound and pharmaceutical composition.

7 cl, 2 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a compound of the formula (I):

wherein R1 is chosen from the following group: (C1-C6)-alkyl, (C2-C6)-alkylidene, (C2-C6)-alkenyl, (C2-C6)-alkynyl, -O-(C1-C6)-alkyl, -O-(C2-C6)-alkenyl; m = 1; C3-C4 mean -CH2-CH or -CH=C, or C4 represents -CH and C3 absents; R2 and R3 represent hydrogen atom (H); or R2, R3, m and C3-C4 form compound of the formula:

; each among R4 and R5 is chosen independently from group comprising H, halogen atom, hydroxy-group, (C1-C6)-alkyl, -O-(C1-C6)-alkyl; L1 and L2 represent biradicals chosen from group comprising -(CR6)=C(R7), -C(R6)=N and -N=C(R6)-, -S-; Y is chosen from group consisting of oxygen atom (O) and two hydrogen atoms; X is chosen from group comprising -C(R6)(R7)-C(R6)(R7)-, -C(R6)=C(R7)-, -O-C(R6)(R7)-, -C(R6)(R7-O-, -S-C(R6)(R7)-, -C(R6)(R7)-S- and -S-. Invention describes compositions comprising compounds of the formula (I), method for enhancing activity of muscarinic receptors of subtype M1, method for treatment of diseases associated with muscarinic receptors.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 2 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: pharmaceutical industry.

SUBSTANCE: invention relates to pharmaceutical kit to produce injection depo-preparation of active arylheterocyclic substance such as ziprazidone and method for production thereof. Claimed kit contains arylheterocyclic substance (ziprazidone) and liquid viscosity-providing carrier. When ziprazidone is non- solubilized said liquid carrier additionally contains solubilizer such as cyclodextrin. Pharmaceutical kit is used in treatment of schizophrenia. Injection ziprazidone depo-preparation provides delivery of active ingredient for long period of time in concentrations effective for schizophrenia treatment.

EFFECT: improved preparation for schizophrenia treatment.

15 cl, 8 tbl, 7 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to triheterocyclic compound of the formula (I): wherein X represents carbon atom; Y represents carbon or nitrogen atom; W represents carbon or nitrogen atom; U represents -CR2, and Z represents -CR2 or nitrogen atom; ring A represents (C5-C6)-cycloalkyl ring or 5-membered heterocyclic ring comprising one nitrogen, oxygen or sulfur atom; R1 represents alkyl, alkenyl, alkynyl, -NR4R5, -OR6 and others; R3 represents phenyl ring substituted with 1-3 substitutes or pyridyl or 1,3-dioxoindanyl ring substituted with 1-2 substitutes, and its pharmaceutically acceptable salts and pharmaceutical composition containing thereof as an active component. Also, invention relates to derivatives of pyrazolopyrimidine and derivatives of pyrrolopyrimidine. Compounds of the formula (I) show antagonistic activity with respect to corticotropin-releasing factor receptors. The compound can be used in treatment and/or prophylaxis of depression, anxiety state, disorders in food intake, post-traumatic stress, ulcerous disease, irritable bowel syndrome, Alzheimer's disease, abuse in drugs using or alcoholic syndrome dependence.

EFFECT: valuable medicinal properties of compounds and pharmaceutical agent.

7 cl, 1 dwg, 24 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to triheterocyclic compound of the formula (I): wherein X represents carbon atom; Y represents carbon or nitrogen atom; W represents carbon or nitrogen atom; U represents -CR2, and Z represents -CR2 or nitrogen atom; ring A represents (C5-C6)-cycloalkyl ring or 5-membered heterocyclic ring comprising one nitrogen, oxygen or sulfur atom; R1 represents alkyl, alkenyl, alkynyl, -NR4R5, -OR6 and others; R3 represents phenyl ring substituted with 1-3 substitutes or pyridyl or 1,3-dioxoindanyl ring substituted with 1-2 substitutes, and its pharmaceutically acceptable salts and pharmaceutical composition containing thereof as an active component. Also, invention relates to derivatives of pyrazolopyrimidine and derivatives of pyrrolopyrimidine. Compounds of the formula (I) show antagonistic activity with respect to corticotropin-releasing factor receptors. The compound can be used in treatment and/or prophylaxis of depression, anxiety state, disorders in food intake, post-traumatic stress, ulcerous disease, irritable bowel syndrome, Alzheimer's disease, abuse in drugs using or alcoholic syndrome dependence.

EFFECT: valuable medicinal properties of compounds and pharmaceutical agent.

7 cl, 1 dwg, 24 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to triheterocyclic compound of the formula (I): wherein X represents carbon atom; Y represents carbon or nitrogen atom; W represents carbon or nitrogen atom; U represents -CR2, and Z represents -CR2 or nitrogen atom; ring A represents (C5-C6)-cycloalkyl ring or 5-membered heterocyclic ring comprising one nitrogen, oxygen or sulfur atom; R1 represents alkyl, alkenyl, alkynyl, -NR4R5, -OR6 and others; R3 represents phenyl ring substituted with 1-3 substitutes or pyridyl or 1,3-dioxoindanyl ring substituted with 1-2 substitutes, and its pharmaceutically acceptable salts and pharmaceutical composition containing thereof as an active component. Also, invention relates to derivatives of pyrazolopyrimidine and derivatives of pyrrolopyrimidine. Compounds of the formula (I) show antagonistic activity with respect to corticotropin-releasing factor receptors. The compound can be used in treatment and/or prophylaxis of depression, anxiety state, disorders in food intake, post-traumatic stress, ulcerous disease, irritable bowel syndrome, Alzheimer's disease, abuse in drugs using or alcoholic syndrome dependence.

EFFECT: valuable medicinal properties of compounds and pharmaceutical agent.

7 cl, 1 dwg, 24 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to triheterocyclic compound of the formula (I): wherein X represents carbon atom; Y represents carbon or nitrogen atom; W represents carbon or nitrogen atom; U represents -CR2, and Z represents -CR2 or nitrogen atom; ring A represents (C5-C6)-cycloalkyl ring or 5-membered heterocyclic ring comprising one nitrogen, oxygen or sulfur atom; R1 represents alkyl, alkenyl, alkynyl, -NR4R5, -OR6 and others; R3 represents phenyl ring substituted with 1-3 substitutes or pyridyl or 1,3-dioxoindanyl ring substituted with 1-2 substitutes, and its pharmaceutically acceptable salts and pharmaceutical composition containing thereof as an active component. Also, invention relates to derivatives of pyrazolopyrimidine and derivatives of pyrrolopyrimidine. Compounds of the formula (I) show antagonistic activity with respect to corticotropin-releasing factor receptors. The compound can be used in treatment and/or prophylaxis of depression, anxiety state, disorders in food intake, post-traumatic stress, ulcerous disease, irritable bowel syndrome, Alzheimer's disease, abuse in drugs using or alcoholic syndrome dependence.

EFFECT: valuable medicinal properties of compounds and pharmaceutical agent.

7 cl, 1 dwg, 24 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 2-oxo-1-pyrrolidine of the formula (I) or their pharmaceutically acceptable salts wherein X means -CA1NR5R6 or -CA1-R8 wherein A1 and A2 mean independently oxygen atom; R1 means hydrogen atom (H), (C1-C20)-alkyl, (C6-C10)-aryl or -CH2-R1a wherein R1a means (C6-C10)-aryl; R3 means H, -NO2, nitrooxy-group, C≡N, azido-group, -COOH, amido-group, (C1-C20)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C6-C10)-aryl, thiazolyl, oxazolyl, furyl, thienyl, pyrrolyl, tetrazolyl, pyrimidinyl, triazolyl, pyridinyl, -COOR11, -COR11 wherein R11 means (C1-C12)-alkyl; R3a means H, (C1-C20)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl or (C6-C10)-aryl; R5 and R6 are similar or different and each means independently H, (C1-C6)-alkyl, and R8 means -OH and wherein each alkyl can be substituted independently with from 1 to 5 substitutes chosen from halogen atom, isothiocyanate, -OH, -NO2, -CN, azido-group, (C3-C6)-cycloalkyl and (C6-C10)-aryl;, and wherein each (C6-C10)-aryl can be substituted independently with from 1 to 5 substitutes chosen from halogen atom, -NH2, -NO2, azido-group, (C1-C6)-alkoxy-group, (C1-C6)-alkyl and (C1-C6)-halogenalkyl, and wherein each alkenyl can be substituted independently with at least one substitute chosen from halogen atom and -OH, and under condition that at least one radical among R and R3a differs from H, and when compound represent a mixture of possible isomers then X means -CONR5R6; A2 means oxygen atom, and R1 means H, -CH3, -C2H5, -C3H7, and when each R1 and R3a means H and A2 means oxygen atom and X means -CONR5R6 then R3 differs from -COOH, -CH, -COOR11, amido-group, naphthyl, phenyl rings substituted with (C1-C6)-alkoxy-group or halogen atom in para-position in naphthyl or phenyl ring. Compounds of the formula (I) can be used in pharmaceutical compositions for treatment of epilepsy, epileptogenesis, convulsions, epileptic seizures, essential tremor and neuropathic pain.

EFFECT: improved method of synthesis, valuable medicinal properties of derivatives and pharmaceutical compositions.

27 cl, 3 tbl, 9 ex

FIELD: medicine, pharmacology, pharmacy.

SUBSTANCE: invention relates to agent based on flesh-colored passionflower (Passiflora incarnate L.) herb extractive substances used as a sedative agent. Agent is made as a tablet and its core comprises flesh-colored passionflower dry alcoholic extract and accessory substance: lactose, potato starch, low-molecular polyvinylpyrrolidone, magnesium basic carbonate and magnesium stearate. Core of a tablet is covered by envelope comprising hydroxypropylmethylcellulose, polyethylene glycol-600, dye azorubin and titanium dioxide and these components are taken in the definite ratio. Method for preparing the sedative agent involves the following steps: flesh-colored passionflower dry sprouts with leaves are treated with alcohol in the ratio raw - extractant = 1:2, dried and prepared extract is mixed with lactose, potato starch and magnesium carbonate. Prepared mixture is wetted with low-molecular polyvinylpyrrolidone followed by successive wet granulation, drying granules, dry granulation, granules are powdered, tabletted and prepared tablet core is covered by envelope. Used raw is ground preliminary and dried at temperature 50-60°C. The expressed pharmacological activity of agent is caused by the presence of complex of biologically active substances of phenolic nature, vitamins, trace elements and other natural compounds.

EFFECT: improved preparing method of agent.

4 cl

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition for controlled release that comprises a medicinal agent, polyethylene oxide with molecular mass 2000000 Da or above and a special size-regulating agent for indicated polyethylene oxide and wherein indicated medicinal agent and size-regulating agent are dispersed uniformly in polyethylene oxide. Also, invention relates to a method for preparing indicated pharmaceutical composition for controlled release and a pharmaceutical preparation for controlled release comprising indicated pharmaceutical composition for controlled release. The pharmaceutical composition with controlled release possesses good uniformity of the content and can be prepared using polyethylene oxide powder particles showing properties suitable for making tablets that is prepared by uniform dispersing a size-regulating agent for polyethylene oxide.

EFFECT: improved and valuable pharmaceutical properties of composition.

32 cl, 1 tbl, 16 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a solid medicinal formulation as a chewing tablet possessing the antacid effect. Proposed pharmaceutical composition comprises magnesium carbonate and calcium carbonate as active components, methylcellulose, talc, stearate, aromatic principles and sorbitol as accessory substances wherein state is represented by magnesium state or calcium state. Invention provides preparing a chewing tablet possessing rapidly active effective antacid effect and can be used for oral intake in case of unexpressed organic pathology of digestive tract including patients with diabetes mellitus. The final technical effect exceeds effect caused by the known properties of components only.

EFFECT: improved and valuable pharmaceutical properties of formulation.

2 cl, 1 ex

FIELD: pharmaceutical industry, in particular, in particular solid pharmaceutical formulations useful in treatment of arterial hypertension and chronic heart failure.

SUBSTANCE: claimed formulation comprises core containing (mass %): inapamide 0.3-2.0; colloidal silica 0.1-2.5; hydroxypropyl cellulose 8-35; vinyl pyrrolidone-vinyl acetate copolymer 1.8-4.5; magnesium stearate 0.1-1.0; lactose 15.0-55.0; and balance: microcrystalline cellulose; and sell dissolvable in stomach and containing (mass %) polyethylene glycol 10.0-17.0; titanium dioxide 11.5-20.5; talk 1.8-6.3; and balance hydroxypropylmethyl cellulose. Method for production of said formulation also is provided.

EFFECT: Agent with gradual releasing of active ingredient; tablets with increased mechanical strength; preparation of improved quality in storage process.

3 cl, 1 tbl, 2 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition used in migraine treatment as a solid dosed medicinal formulation for the peroral administration that comprises 5-HT1-agonist sumatriptan or its pharmaceutically active salt or solvate as an active component (in the amount 20-150 mg of sumatriptan as a base) and a main component of a carbonated pair, a loosening agent and an insoluble excipient wherein the amount of the main component id from about 5 to about 50%% by mass, the amount of a loosing component is from about 0.5 to about 10% by mass, and the amount of insoluble excipient is from about 35 to about 80% by mass. Also, invention relates to using the proposed composition in migraine treatment. The composition can be used orally as a whole and provides the curative effect after rapid absorption typical for carbonated compositions.

EFFECT: improved and valuable medicinal and pharmaceutical properties of composition.

8 cl, 6 tbl, 3 dwg, 16 ex

FIELD: medicine.

SUBSTANCE: invention relates to two-layered solid composition including a) the first layer of direct action containing effective antiallergic amount of desloratadine and at least one pharmaceutically acceptable carrier and b) the second layer of prolonged action containing effective amount of nasal anti-oedema agent and pharmaceutically acceptable carrier, wherein composition contains less than 2 % of desloratadine deterioration products. Composition is stable in administration of one or two times per day.

EFFECT: new composition for treatment and/or amelioration of prodromes or symptoms associated with common cold and allergic and/or phlogistic skin or pipe conditions.

28 cl, 1 dwg, 6 ex

FIELD: pharmaceutical industry.

SUBSTANCE: claimed composition for sublingual application contains apomorphine as active ingredient and succinic acid as apomorfine stabilizer and filler, as well as other additives.

EFFECT: sublingual tablet with sufficient strength and resolvability.

4 cl, 1 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: method involves administering macrolide preparation of azithromycin. The drug is applied in concentrations 10 and 30 mg/kg once a day during 7 days. Then, skin flap necrosis zone dimensions are measured and lipid peroxidation intensity is determined.

EFFECT: wide range of functional applications.

1 tbl

FIELD: medicine, pharmaceutical technology, pharmacy.

SUBSTANCE: invention relates to producing solid combined medicinal formulations of preparations exhibiting an antihypertensive effect, increasing heart blow-out index and enhancing tolerance to physical load in patient with the congestive cardiac insufficiency. The proposed medicinal agent comprises the following components, wt.-%: perindopril erbumine, 0.6-7.0; microcrystalline cellulose, 12.0-35.0; magnesium stearate, 0.3-1.7; aerosil, 0.1-1.0; croscarmelose-sodium, 1.1-7.0, and lactose, the balance. Also, invention discloses a method for preparing the medicinal formulation. Invention reduces loss of perindopril in process for the formulation preparing, retaining the parent properties of perindopril erbumine and enhancing biological availability of agent.

EFFECT: enhanced and valuable properties of agent, improved preparing method.

3 cl, 2 tbl, 2 ex

FIELD: medicine, pharmaceutical technology, pharmacy.

SUBSTANCE: invention relates to a medicinal formulation used in treatment of lung, moderate and severe infections of lower respiratory ways, organs of otorhinolaryngology sphere, urinary ways, kidneys, genital organs, skin and soft tissues caused by sensitive strains of microorganisms. The medicinal formulation consists of a core and envelope wherein a core comprises the following components, wt.-%: levofloxacin, 60-69; crospovidone, 2.9-4.5; magnesium stearate, 0.1-1.0; lauryl sulfate sodium, 0.5-2.0; polyvinylpyrrolidone, 2.0-3.5; microcrystalline cellulose, the balance; envelope comprises the following components, wt.-%: yellow iron oxide, 0.05-0.1; red iron oxide, 0.05-0.1; hydroxypropylcellulose, 35.0-42.0; polyethylene glycol, 10.0-20.0; titanium dioxide, 4.8-9.0, and hydroxypropylmethylcellulose, the balance. Also, invention discloses a method for making this medicinal formulation. Invention provides rapid release of active substance in digestive tract and high strength of the proposed medicinal formulation.

EFFECT: improved preparing method, enhanced and valuable medicinal and pharmaceutical properties of formulation.

5 cl, 1 tbl, 3 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to a medicinal formulation consisting of a core comprising the following components, wt.-%: trimetazidine dihydrochloride, 9.0-32.0; hydroxypropylcellulose, 3.0-10.5; hydroxyethylcellulose, 18.5-67.2; sodium alginate, 0.1-0.6; calcium phosphate dihydrate, 19.0-28.5; magnesium stearate, 0.5-2.0; talc, 0.5-2.0, and envelope comprising the following components, wt.-%: one component chosen from the group including hydroxypropylcellulose, water-soluble methylcellulose or hydroxypropylcellulose, 0.6-2.7; Tween-80, 0.3-1.2; pigment titanium dioxide, 0.1-1.0 and red iron oxide, 0.1-0.8. Method for preparing the medicinal formulation is carried out by wet granulation, tabletting prepared granules and applying the envelope from an aqueous suspension by spraying preferably. Release of trimetazidine dihydrochloride in the body from the new proposed formulation is carried out for 8 h that provides the constant level of the preparation in blood.

EFFECT: improved preparing method, valuable pharmaceutical properties of formulation.

3 cl, 2 tbl, 1 ex

FIELD: chemistry of metalloorganic compounds, medicine, oncology.

SUBSTANCE: invention relates to novel chemical compounds, namely, to complexes of palladium with heterocyclic ligands of the general formula (I): wherein R1 means-NH, oxygen atom (O), -CH2; R2 means two hydrogen atoms (2H), O; R3 means hydrogen atom H, CH3, CH2-CH2-NH2,-(CO)-CH3; X means chlorine (Cl), bromine (Br) atom; n = 1; m = 1 if R1 means -NH, O; R2 means 2H; R3 means H, CH3, CH2-CH2-NH2, -(CO)-CH3; n = 2; m = 1 if R1 means O, -CH2; R2 means O, 2H; R3 means H, CH3, -(CO)-CH3; n = 2; m = 3 if R1 means -NH; R2 means 2H; R3 means CH2-CH2-NH2 eliciting pharmacological, in particular, anti-tumor activity. Proposed compounds possess high activity and characterized by reduced toxicity as compared with anti-tumor preparations with platinum complexes.

EFFECT: valuable medicinal properties of complexes.

4 cl, 2 tbl, 10 ex

Up!