Sustained release solid therapeutic agent

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, and represents a sustained release solid therapeutic agent containing a combination of praziquantel with emodepside, polyvinylpyrrolidone and/or a polyvinylpyrrolidone derivative in an amount of 10 to 50 wt %, polyvinylpyrrolidone and/or the polyvinylpyrrolidone derivative is a mixture of one short-chain polyvinylpyrrolidone and one polyvinylpyrrolidone or the polyvinylpyrrolidone derivative with longer chains, and at least one excipient in an amount of 5 to 80 wt %.

EFFECT: sustained release of active substances and no lump formation in the gastrointestinal tract if two or more tablets taken.

4 cl, 7 ex, 4 dwg

 

The present invention relates to a solid drug with a slow release of active substances that can be used primarily for the treatment of animals.

Drugs with a slow (controlled) release of active ingredients rarely used in veterinary medicine, primarily for the treatment of cats and dogs, although drugs of this type in different options of technical performance are the most widely used in human medicine. One of the main reasons for this is that animals, especially cats and dogs differ from humans in relation to the duration of drugs in the gastro-intestinal tract, the effects of food products, the influence of habitual ways of eating, the physiological characteristics of the stomach, including its size and pH, the type present in the intestinal enzymes, permeability of the gastrointestinal tract and its absorbing active substance sites [S. C. Sutton, Adv. Drug delivery reviews, 56 (2004) 1383-1398]. Physiological differences between dogs and humans is described in detail in the literature [Dressman, Pharm Res., 3 (1986) 123-131; Schneider and others, J. Med. Chem., 42 (1999) 5072]. If an animal chews the usual oral accepted tablet with prolonged action, or otherwise transfers it to a ground state, the CR�zvychaino rapid release of active substance, and the immediate goal of taking these pills is not achieved. The absorption of the active substance (in other words pharmaco-kinetic profile) due chewable tablets may significantly change. In this regard, strive to create suitable for such cases, the drug, the degree of grinding which has the least possible impact on the absorption of the active substance. The development of such medicines is applicable for animals, is a very complex technical problem for pharmacists. However, note also that the mechanical impact, for example, in the dog's stomach is much higher compared to the human stomach.

In the international application WO 2004/014346 describes the sustained-release tablet of cuprofen that contain hydrophilic polymers methocel (hydroxypropyl methylcellulose), crystalline polyethylene oxide and carbopol. The principle of action of these tablets is based on the fact that they contain microparticles, capable of controllably releasing the active substance. These drugs are very hard to produce, and it remains unclear whether it is possible to ensure the proper kinetics of active substance release in the gastro-intestinal tract of the animal without compromising bioavailability.

�berating the problem for pharmacists due to the fact, what is the duration of medicines in the stomach and the digestive tract of animals subject to significant fluctuations. As shown, for example, Fig.7 and 8, the above-cited publications Sutton, the duration of the drug in the gastro-intestinal tract hound dogs vary considerably in the case of taking a drug on an empty stomach or after feeding. Sutton reports that the time spent about 80% of tablets in the digestive tract is more than 24 hours. Based on this fact, Sutton concludes that the usual total dose can be absorbed in a dog's body without premature excretion in the feces due to the reception of preparations of prolonged action with a defined in vitro by the time of release of active substances constituting less than 24 hours. In addition, the duration of the drug in the stomach depends on the size of the drug, as well as the kind and breed of the corresponding animal [see, for example, and Fix others, Pharm. Res., 10 (1993) 1087-1089]. While pharmacists seek to develop drugs suitable for ingestion by animals of different species and breeds.

Another problem for pharmacists is that the active substance can often be absorbed mainly only in certain limited areas of the gastrointestinal tract. In �inappropriate absorption of the active substance, for example, only in the small intestine, the drug active substance must be able to fully release the active substance in the small intestine. Fluctuations in the duration of the drug in the GI tract can affect the biological availability of the active substance. Digestive tract, for example, dogs at certain intervals of time subject to peristaltic movement, which has an impact on the duration of the drug in the gastro-intestinal tract. In addition, the duration of the drug in the stomach depends on the type and number of adopted animals for food, and even from the size of the output orifice of the stomach.

The result of the above issues is the current lack of on the market is suitable for treatment of dogs with oral drugs with controlled release of active ingredients. In any case, the development of drugs of this type, suitable for treating, for example, cats and/or dogs, is a very difficult task, which is poorly covered in the literature.

Known numerous opportunities to provide a delayed release of active substances. Experts in the pharmaceutical field usually prefer� matrix tablets which contain forming a hydrophilic gel polymers, such as cellulose ethers (hydroxypropyl cellulose or hydroxypropylmethyl cellulose), since such tablets can be produced with conventional pharmaceutical vehicles with a wide possibility of variation of the production conditions. As a result chewable similar tablets, for example, a dog swelling gel-forming polymer and the resultant direct fast release of the active substance.

Depending on breed animals, such as dogs, can be of different sizes and weight. Ensuring the accurate correspondence between the drug dose and the size of the animal is hardly possible, as it would require extremely costly production and marketing. In regard to animals with small dimensions, usually are pills that are designed for larger animals. In such cases, larger animals have to give two or more pills. When using the above conventional technology for the production of hydrophilic matrix tablets containing gel-forming polymers such as cellulose ethers, tablets swell in the aqueous environment of the gastrointestinal tract, resulting in a gel�curve shell. The results made the authors of the present application studies show that these gel membranes stick together with each other, which is accompanied by the formation in the gastrointestinal tract of large lumps. The surface of this ball is much less than the total surface of the individual swollen tablets. As a consequence, the rate of release of active substance from such lumps are much lower compared to the rate of release of individual pills. Thus, the observed in vivo release of active ingredient from the gel matrix is characterized by a lack of reproducibility.

In accordance with the recommendations of the prior art are acceptable for dogs are tablets with prolonged action, the active substance release which should last up to 24 hours, since the passage in about 80% of the tablets through the gastrointestinal tract is at least 24 hours. However, the authors of the present application have unexpectedly found that if the dogs even on an empty stomach tablets on the basis of simple esters of cellulose which release in vitro over 80% of active ingredient within about 12 hours, in animal faeces detect only partially swollen tablets with a dry core. This leads to decrease bio-availability. The problem�s are even enhanced in the case of taking a few pills usually applied for the purpose of suitable dosing for large animals. While in the feces also find clumps of agglomerated pellets.

In the publication Mcinnes and others (Pharm Res., October 2007) reported the results of the dog study (after feeding and fasting) two matrix tablets with different rates of release of active substance in vitro. The authors of this publication could not find a simple correlation between the release of the active substance in vitro and in vivo. Thus, it is not easy to design a tablet with a prolonged effect that increasing the availability of all the contained amount of active substance to excretion with feces and at the same time would not suffer the disadvantage that receive more than one such pills.

Based on the foregoing, the present invention was based on the task to develop a tablet with delayed release of active substances, which fully destroyed in the gastro-intestinal tract, with the greatest possible fullness of releasing the active ingredients over a certain period of time regardless of the time of taking the pill, that is, after feeding the animal or on an empty stomach. The execution of the specified requirements would give to pet owners and veterinarians �werenot to secure such drugs in the absence of the destroyed parts of the tablet in the feces of the animal. First of all, should seek to develop a matrix system, preferably capable of releasing at least 80% of the total amount of active substance during the interval from 1 to 6 hours, and in the case of receiving two or more pills in the aqueous environment of the gastrointestinal tract, there should be no lumps. In addition, it should be possible simple manufacture of the medicinal product specified type in is usually used in the pharmaceutical industry machines.

Thus, an object of the present invention is a solid drug with a slow release of active substances, which contains:

and. at least one pharmaceutically active substance,

b. polyvinylpyrrolidone with an indicator To at least 17,

C. at least one filler.

According to the invention as pharmaceutically active substances, in principle, any suitable respective pharmaceutically active chemical compounds.

According to a preferred embodiment of the invention it is about the use of anthelmintic active ingredients.

Thus a preferred group of anthelmintic active ingredients include depsipeptide.

Depsipeptide � principle are analogues of peptides and different from the last, one or more structural elements α-amino acid is replaced by structural elements (structural elements) α-hydroxycarbonic acid. According to the invention preferably use a circular depsipeptide with 18 to 24 ring atoms, especially with 24 ring atoms.

To depsipeptides with 18 ring atoms include compounds of the General formula (I):

in which

R1, R3and R5independently from each other, respectively represent hydrogen, unbranched or branched alkyl containing up to eight carbon atoms, hydroxyalkyl, alkanoyloxy, alkoxyalkyl, aryloxyalkyl, mercaptoethyl, alkylthiomethyl, alkylsulfonyl-Kil, alkylsulfonyl, carboxylic, alkoxycarbonylmethyl, arylalkanolamine, carbamoylethyl, aminoalkyl, alkilani-nalkyl, dialkylaminoalkyl, guanidinate, which may optionally be substituted with one or two benzyloxycarbonylamino ostatkami or one, two, three or four alkyl residues, alkoxycarbonylmethyl, 9 fluorenylmethyl-carbonylmethyl, alkenyl, cycloalkyl, cycloalkenyl and arylalkyl, optionally substituted by halogen, hydroxy, alkyl or alkoxy,

R2, R4and R6independently from each other, respectively, the m�t hydrogen, unbranched or branched alkyl containing up to eight carbon atoms, hydroxyalkyl, mercaptoethyl, alkanoyloxy, alkoxyalkyl, aryloxyalkyl, alkylthiomethyl, alkylsulfonyl, alkylsulfonyl, carboxylic, alkoxycarbonyl, aryl-alkoxycarbonylmethyl, carbamoylethyl, aminoalkyl, alkylamino-Kil, dialkylaminoalkyl, alkoxycarbonylmethyl, alkenyl, cycloalkyl or cycloalkenyl, and aryl or arylalkyl, optionally substituted by halogen, hydroxy, alkyl or alkoxy,

as well as optical isomers and racemate of these compounds.

Preferred are compounds of formula (I):

in which

R1, R3and R5independently from each other, respectively, denote unbranched or branched alkyl with 1-8 carbon atoms, especially methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, second-hexyl, heptyl, isoheptyl, sec-heptyl, tert-heptyl, octyl, isooctyl or sec-octyl, hydroxyalkyl with 1-6 carbon atoms, especially gidroximetil or 1-hydroxyethyl, alkanoyloxy with 1-4 carbon atoms in alkanoyloxy and 1-6 carbon atoms in the alkyl, especially acetoxymethyl or 1-acetoxyethyl, alkoxyalkyl with 1-4 carbon atoms in the alcohol�C and 1-6 carbon atoms in the alkyl, first of all methoxymethyl or 1-methoxyethyl, arylalkylamines with 1-4 carbon atoms in alkyloxy and 1-6 carbon atoms in the alkyl, especially benzoyloxymethyl or 1-benzyloxyethyl, mercaptoethyl with 1-6 carbon atoms, especially mercaptomethyl, alkylthiols with 1-4 carbon atoms in alkylthio and 1-6 carbon atoms in the alkyl, especially methylthioethyl, alkylsulfonyl with 1-4 carbon atoms in alkylsulfanyl and 1-6 carbon atoms in the alkyl, especially methylsulfinylbutyl, alkylsulfonyl with 1-4 carbon atoms in alkylsulfonyl and 1-6 carbon atoms in the alkyl, especially methylsulfonylmethyl, carboxyethyl with 1-6 carbon atoms, first of all, carboxymethyl or carboxyethyl, alkoxycarbonyl with 1-4 carbon atoms in alkoxycarbonyl and 1-6 carbon atoms in the alkyl, especially methoxycarbonylmethyl or ethoxycarbonylethyl, arylalkanolamine with 1-4 carbon atoms in Allakaket-carbonyl and 1-6 carbon atoms in the alkyl, especially benzylic-icarbonell, carbamoylethyl with 1-6 carbon atoms in the alkyl, especially carbamoylmethyl or carbamoylethyl, aminoalkyl with 1-6 carbon atoms, particularly aminopropyl or aminobutyl, acylaminoalkyl with 1-4 carbon atoms in alkylamino and 1-6 carbon atoms in the alkyl, especially methylaminopropyl or methylamino-butyl, dialkylaminoalkyl with 1-4 at�Mami carbon in alkylamino and 1-6 carbon atoms in the alkyl, first of all, dimethylaminopropyl or dimethylaminomethyl, Gwendolyn with 1-6 carbon atoms in the alkyl, especially grandprari, alkoxycarbonylmethyl with 1-4 carbon atoms in alkoxycarbonyl and 1-6 carbon atoms in the alkyl, especially tert-butoxycarbonylamino or tert-butoxycarbonylamino, 9 fluorenylmethoxycarbonyl-alkyl with 1-6 carbon atoms in the alkyl, especially 9- or 9 fluorenylmethyl-carbonylmethyl, alkenyl with 2-8 carbon atoms, especially vinyl, allyl or butenyl, cycloalkyl with 3-7 carbon atoms, especially cyclopentyl, cyclohexyl or cycloheptyl, cycloalkyl with 3-7 carbon atoms in cycloalkyl and 1-4 carbon atoms in the alkyl, especially cyclopentylmethyl, cyclohexylmethyl or cyclohe-teletel and phenylalkyl with 1-4 carbon atoms in the alkyl, especially phenylmethyl, which optionally can be substituted with residues selected from the group comprising halogen, especially fluorine, chlorine, bromine or iodine, hydroxy, alkoxy with 1-4 carbon atoms, especially methoxy or ethoxy, and alkyl with 1-4 carbon atoms, especially methyl.

R2, R4and R6independently from each other, respectively, denote unbranched or branched alkyl with 1-8 carbon atoms, especially methyl, ethyl, propyl,�propyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, second-hexyl, heptyl, isoheptyl, sec-heptyl, tert-heptyl, octyl, ISO-octyl or sec-octyl, hydroxyalkyl with 1-6 carbon atoms, especially gidroximetil or 1-hydroxyethyl, alkanoyloxy with 1-4 carbon atoms in alkanoyloxy and 1-6 carbon atoms in the alkyl, especially acetoxymethyl or 1-acetoxyethyl, alkoxyalkyl with 1-4 carbon atoms in the alkoxy and 1-6 carbon atoms in the alkyl, first of all methoxymethyl or 1-methoxyethyl, arylalkylamines with 1-4 carbon atoms in alkyloxy and 1-6 carbon atoms in the alkyl, especially benzoyloxymethyl or 1-benzyloxyethyl, mercaptoethyl with 1-6 carbon atoms in the alkyl, especially mercaptomethyl, alkyl-thioalkyl with 1-4 carbon atoms in alkylthio and 1-6 carbon atoms in the alkyl, especially methylthioethyl, alkylsulfonyl with 1-4 carbon atoms in alkylsulfanyl and 1-6 carbon atoms in the alkyl, especially methylsulfinylbutyl, alkylsulfonyl with 1-4 carbon atoms in alkylsulfonyl and 1-6 carbon atoms in the alkyl, especially methylsulfonylmethyl, carboxyethyl with 1-6 carbon atoms in the alkyl, especially carboxymethyl or carboxyethyl, al-oxycarbonyl with 1-4 carbon atoms in alkoxycarbonyl and 1-6 carbon atoms in the alkyl, especially methoxycarbonylmethyl or etox�carbonylethyl, arylalkanolamine with 1-4 carbon atoms in arylalkanolamine and 1-6 carbon atoms in the alkyl, especially benzyloxycarbonylamino, carbamoylethyl with 1-6 carbon atoms in the alkyl, especially carbamoylmethyl or carbamoylethyl, aminoalkyl with 1-6 carbon atoms, particularly aminopropyl or aminobutyl, acylaminoalkyl with 1-4 carbon atoms in alkylamino and 1-6 carbon atoms in the alkyl, especially methylaminopropyl or methylaminomethyl, dialkylaminoalkyl with 1-4 carbon atoms in alkylamino and 1-6 carbon atoms in the alkyl, especially dimethyl-aminopropyl or dimethylaminomethyl, alkenyl with 2-8 carbon atoms, especially vinyl, allyl or butenyl, cycloalkyl with 3-7 carbon atoms, especially cyclopentyl, cyclohexyl or cycloheptyl, cycloalkyl with 3-7 carbon atoms in cycloalkyl and 1-4 carbon atoms in the alkyl, especially cyclopentylmethyl, cyclohexyl-methyl or cycloheptylmethyl, phenyl, and phenylalkyl with 1-4 carbon atoms in the alkyl, especially phenylmethyl, which optionally can be substituted with residues selected from the group comprising halogen, especially fluorine, chlorine bromine or iodine, hydroxy, alkoxy with 1-4 carbon atoms, especially methoxy or ethoxy, and alkyl with 1-4 carbon atoms, primarily methyl, as well as optical isomers and racemate of these compounds.

Special�about preferred are compounds of formula (I), in which

R1, R3and R5independently from each other, respectively, denote unbranched or branched alkyl with 1-8 carbon atoms, especially methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, second-hexyl, heptyl, isoheptyl, sec-heptyl, octyl, isooctyl or sec-octyl, hydro-cialkis with 1-6 carbon atoms, especially gidroximetil or 1-hydroxyethyl, alkanoyloxy with 1-4 carbon atoms in alkanol-hydroxy and 1-6 carbon atoms in the alkyl, first of all acetoxymethyl or 1-acetoxyethyl, alkoxyalkyl with 1-4 carbon atoms in the alkoxy and 1-6 carbon atoms in the alkyl, especially methoxymethyl or 1-methoxyethyl, arylalkylamines with 1-4 carbon atoms in alkyloxy and 1-6 carbon atoms in the alkyl, especially benzoyloxymethyl or 1-benzyloxyethyl, alkoxycarbonylmethyl with 1-4 carbon atoms in alkoxycarbonyl and 1-6 carbon atoms in the alkyl, especially tert-butoxycarbonylamino or tert-butoxycarbonyl-delaminate, alkenyl with 2-8 carbon atoms, especially vinyl or allyl, cycloalkyl with 3-7 carbon atoms, first of all cyclo-pentyl, cyclohexyl or cycloheptyl, cycloalkyl with 3-7 carbon atoms in cycloalkyl and 1-4 carbon atoms in the alkyl, especially cyclopentylmethyl, cyclohexylmethyl or cyclohepta�methyl, and phenylalkyl with 1-4 carbon atoms in the alkyl, especially phenylethyl, which may optionally be substituted by one or more identical or different residues above,

R2, R4and R6independently from each other, respectively, denote unbranched or branched alkyl with 1-8 carbon atoms, especially methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, second-hexyl, heptyl, isoheptyl, sec-heptyl, tert-heptyl, octyl, isooctyl or sec-octyl, hydroxyalkyl with 1-6 carbon atoms in the alkyl, especially gidroximetil, arylalkylamines with 1-4 carbon atoms in alkyloxy and 1-6 carbon atoms in the alkyl, first of all benzoyloxymethyl or 1-benzyloxyethyl, carboxyethyl with 1-6 carbon atoms in the alkyl, especially carboxymethyl or carboxyethyl, al-oxycarbonyl with 1-4 carbon atoms in alkoxycarbonyl and 1-6 carbon atoms in the alkyl, especially methoxycarbonylmethyl or ethoxycarbonylethyl, arylalkanolamine with 1-4 carbon atoms in arylalkanolamine and 1-6 carbon atoms in the alkyl, especially benzyloxycarbonylamino, acylaminoalkyl with 1-4 carbon atoms in alkylamino and 1-6 carbon atoms in the alkyl, especially methylaminopropyl or methylaminomethyl, dialkylaminoalkyl � 1-4 carbon atoms in alkylamino and 1-6 carbon atoms in the alkyl, first of all, dimethylaminopropyl or dimethylaminomethyl, alkenyl with 2-8 carbon atoms, especially vinyl, allyl or butenyl, cycloalkyl with 3-7 carbon atoms, especially cyclopentyl, cyclohexyl or cycloheptyl, cycloalkyl with 3-7 carbon atoms in cycloalkyl and 1-4 carbon atoms in the alkyl, first of all, cyclopen-teletel, cyclohexylmethyl or cycloheptylmethyl, phenyl, and phenylalkyl with 1-4 carbon atoms in the alkyl, especially phenylethyl, which may optionally be substituted by one or neskolko odinakowymi or different above-mentioned residues,

as well as optical isomers and racemate of these compounds.

Even more preferred are compounds of formula (I) in which:

R1, R3and R5independently from each other, respectively, denote unbranched or branched alkyl with 1-8 carbon atoms, especially methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, second-hexyl, heptyl, isoheptyl, sec-heptyl, octyl, isooctyl or sec-octyl, alkenyl with 1 to 8 carbon atoms, especially allyl, cycloalkyl with 3-7 carbon atoms in cycloalkyl and 1-4 carbon atoms in the alkyl, especially cyclohexylmethyl, and phenylalkyl with 1-4 carbon atoms in the alkyl, especially phenylmethyl,

R2, R4/sup> and R6independently from each other, respectively, denote unbranched or branched alkyl with 1-8 carbon atoms, especially methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, sec-pentyl, hexyl, isohexyl, second-hexyl, heptyl, isoheptyl, sec-heptyl, octyl, isooctyl or sec-octyl, alkenyl with 2-8 carbon atoms, especially vinyl or allyl, cycloalkyl-alkyl with 3-7 carbon atoms in cycloalkyl and 1-4 carbon atoms in the alkyl, especially cyclohexylmethyl, and phenylalkyl with 1-4 carbon atoms in the alkyl, especially phenylethyl, which may optionally be substituted by one or neskolko same or different above-mentioned residues,

as well as optical isomers and racemate of these compounds.

Residues R1-R6in the compounds of the General formula (I):

in particular, can mean:

R1R2R3R4R5R6
Snresn2IU-cyclohexylSnresn2IU-Me Snresn2IU-Me
Snresn2IU-cyclohexylSnresn2IU-MeSnresn2IU-cyclohexyl
Snresn2IU-CH2-PheSnresn2IU-MeSnresn2IU-Me
Snresn2IU-CHz-PheSnresn2IU-MeSnresn2IU-CH2-Phe
Snresn2IU-(CH2)3-IUSnresn2IU-MeSnresn2IU-Me

-Snme2 -Me
R1R2R3R4R5R6
-CHMeCH2Me-(CH2)3-IU-CHMeCH2Me-Me-CHMeCH2Me-(CH2)3-IU
-Snme2-CH2-Phe-CHMeCH2Me-Me-CHMeCH2Me-Me
-CH2-Phe-Snme2-CH2-Phe-Snme2-CHMeCH2Me-Snme2
-CH2Snme2-CH2-Phe-CH2CHMe2-Me-CH2Snme2-CH2-Phe
-(CH2)3-IU-Me-CHMeCH2Me-Me-CHMeCH2Me-Me
-Snme2-Me-Snme2-Me-Me
-CH2-IU-Me-CH2-IU-Me-CH2-IU-Me
-(CH2)2-IU-Me-(CH2)2-Me-Me-(CH2)2-Me-Me
-(CH2)3-IU-Me-(CH2)3-IU-Me-(CH2)3-IU-Me
-CH2-CH=CH2-Me-CH2-CH=CH2-Me-(CH2)-CH=CH2-Me
-CHMeCH2Me-Me-CHMeCH2Me-Me-CHMeCH2Me-CH2-IU
-CHMeCH2Me-Me-CHMeCH2Me-CHMeCH2Me-(CH2)2-Me
-CHMeCH2Me-Me-CHMeCH2Me-Me-CHMeCH2Me-(CH2)3-IU
-CHMeCH2Me-Me-CHMeCH2Me-Me-CH2IU-Me
-CHMeCH2Me-Me-CHMeCH2Me-Me-(CH2)2-IU-Me
-cyclohexyl-Me-cyclohexyl-Me-cyclohexyl-Me
-CH2Snme2-cyclohexyl-CH2CHMe2-Me-CH2Snme2-cyclohexyl
-CH2Snme2-cyclo�exil -CH2Snme2-Me-CH2Snme2-Me
-CHMeCH2Me-Snme2-CHMeCH2Me-Snme2-CHMeCH2Me-Me
-CH2-Phe-Me-CH2-Phe-Me-CH2-Phe-Me
-cyclohexyl-Me-cyclohexyl-Me-cyclohexyl-Me
-Snme2-Snme2-Snme-Me-Snme2-Me
-Snme2-Snme2-CHMe2-Snme2-Snme2-Me
-CH2-IU -Snme2-CH2IU-Me-CH2-IU-Me
-CH2-IU-Snme2-Snme2-Snme2-CH2-IU-Me
-(CH2)2-IU-Snme2-(CH2)2-IU-Me-(CH2)2-IU-Me
-(CH2)2-IU-Snme2-(CH2)2-Me-Snme2-(CH2)2-IU-Me
-(CH2)3-IU-Snme2-(CH2)3-IU-Me-(CH2)3-IU-Me
-(CH2)3-IU-Snme2-(CH2)3-IU-Snme2 -(CH2)3-IU-Me
-CH2-CH=CH2-Snme2-CH2-CH=CH2-Me-CH2-CH=CH2-Me
-CH2-CH=CH2-Snme2-CH2-CH=CH2-Snme2-CH2-CH=CH2-Me
-Me-Me-CHMeCH2Me-Me-CH2-IU-Me
-Me-Me-CHMeCH2Me-Me-(CH2)3-IU-Me

wherein Me means methyl and Phe means phenyl.

In addition, suitable depsipeptide is known from European patent EP 0 382 173 compound PF 1022 formula (IIA):

Suitable depsipeptide are also compounds known from international application WO 93/19053.

To p�a last resort, first of all, include compounds of formula (IIb):

in which

Z means N-morpholinyl, amino, monoamino or dimethylamino.

In addition, suitable depsipeptide are compounds of formula (IIC):

in which

R1, R2, R3, R4independently from each other denote hydrogen, alkyl with 1-10 carbon atoms or aryl, especially phenyl, which is optionally substituted by hydroxy, alkoxy with 1-10 carbon atoms or a halogen.

Compounds of General formulas (I) and (IIA), (IIb) and (IIc) are known and can be obtained by methods described in European patent application EP-A-382 173, German patent applications DE-A 4 317 432, DE-A 4 317 457 and DE-A 4317458, as well as in European patent applications EP-A-634 408, EP-A-718293, EP-A-872481, EP-A-685 469, EP-A-626 375, EP-A-664 297, EP-A-669343, EP-A-787141, EP-A-865 498 and EP-A-903 347, or similar methods.

To cyclic depsipeptides with 24 ring atoms include compounds of the General formula (lid):

in which

R1a, R2a, R11aand R12aindependently from each other correspondingly denote alkyl with 1-8 carbon atoms, halogenated with 1-8 carbon atoms, cycloalkyl with 3-6 carbon atoms, aralkyl or aryl,

R33, R53, R73, R93independently from each other will sootvetstvenno hydrogen, unbranched or branched alkyl with 1-8 carbon atoms, which may optionally be substituted by hydroxy, alkoxy with 1-4 carbon atoms, carboxymethyl, grouping, carboxamido, grouping, imidazolium, indolium, guanidino, balance-SH or alkylthio with 1-4 carbon atoms, and aryl or aralkyl which may be substituted by halogen, hydroxy, alkyl with 1-4 carbon atoms or alkoxy with 1-4 carbon atoms,

R4a, R6a, R8a, R10aindependently from each other, respectively represent hydrogen, an unbranched alkyl with 1-5 carbon atoms, alkenyl with 2-6 carbon atoms or cycloalkyl with 3-7 carbon atoms, which optionally can be substituted by hydroxy, alkoxy with 1-4 carbon atoms, carboxymethyl, carboxamido, imidazolium, indolium, guanidino, balance-SH or alkylthio with 1-4 carbon atoms, and aryl or aralkyl which may be substituted by halogen, hydroxy, alkyl with 1-4 carbon atoms or alkoxy with 1-4 carbon atoms,

as well as optical isomers and racemate of these compounds. Preferably used compounds of the formula (IId) in which:

R13, R213, R113and R123independently from each other, respectively represent methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl or f�Neal, which is optionally substituted by halogen, alkyl with 1-4 carbon atoms, hydroxyl or alkoxy with 1-4 carbon atoms, and benzyl, or phenylethyl, which may be specified by the substituted phenyl residues, and

R3A-R10Asuch as indicated above.

Especially preferred are compounds of formula (IId) in which:

R1a, R2a, R11aand R12aindependently from each other denote methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl group,

R3a, R5a, R7a, R9amean hydrogen, unbranched or branched alkyl with 1-8 carbon atoms, especially, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl or tert-butyl group, which optionally can be substituted by alkoxy with 1-4 carbon atoms, especially methoxy or ethoxy, imidazolyl, indolium or alkylthio with 1-4 carbon atoms, especially methylthio or ethylthio, as well as phenyl, benzyl or phenethyl which optionally can be substituted by halogen, especially chlorine, and

R4a, R6a, R8a, R10aindependently from each other, respectively represent hydrogen, methyl, ethyl, n-propyl, n-butyl, vinyl, or cyclohexyl, which are optionally can be substituted by methoxy, ethoxy, imidazolyl, indolium, methylthio or ethylthio, and also isopropyl, W�p - butyl or optionally substituted by halogen phenyl, benzyl or phenylethyl.

Compounds of formula (IId) can also be obtained by methods described in European patent application EP-A-382 173, German patent applications DE-A 4 317 432, DE-A 4 317 457 and DE-A 4 317 458, as well as in European patent applications EP-A-634408, EP-A-718293, EP-A-872481, EP-A-685469, EP-A-626375, EP-A-664 297, EP-A-669 343, EP-A-787 141, EP-A-865 498 and EP-A-903 347.

According to the invention is even more preferred depsipeptide include PF 1022 A (compound of formula (In)) and emodepside (PF 1022-221, the compound of formula (HB), in which both residue Z mean morpholinyl). International nonproprietary name "emodepside" is used to denote connection with the systematic name of cyclo[(R)-lactol-N-methyl-1-leucyl-(R)-3-(p-morpholinoethyl)-lactol-N-methyl-L-leucyl-(R)-lactol-N-methyl-L-leucyl-(R)-3-(p-morpholinoethyl)lactol-N-methyl-L-leucyl.

Other suitable anthelmintic active ingredients are praziquantel or epsiprantel. Both of these compounds has long been known as active ingredients against internal parasites (see, for example, U.S. patent US 4 661 489 for epsiprantel and U.S. patent US 4 411 001 for praziquantel). Contains praziquantel drugs can be purchased on the market, for example, under the trade name Droncit®. In accordance with the present invention it is preferred to use prusik�antela.

According to a particularly preferred embodiment of the invention, depsipeptide can be used in combination with praziquantel or epsiprantel, the preferred partner of depsipeptide is praziquantel.

The above-mentioned preferred and particularly preferred depsipeptide are preferred and especially preferred when used in combination with other active ingredients.

According to another preferred embodiment of the invention proposed in the invention of solid medicines contain a combination of praziquantel with the compound PF 1022 A.

According to another even more preferred embodiment of the invention proposed in the invention of solid medicines contain a combination of praziquantel with emodepside.

Other suitable active substances include macrocycle-ical lactones, particularly the avermectins, dihydroavermectin (hivert-machine) or milbemycines. These compounds possess antihelium-mintim action and at the same time are characterized by more or less strong action against copersito, for example, insects or ticks.

The avermectins primarily include eight representatives of active substances of this type: A1a, A1b, A2aAnd 2bB1aIn1bIn2Aand In2b. In practice, the use, for example, called abamectin mixture mainly containing avermectins B1. The avermectins include, for example, doramectin and selamectin.

The products of hydrogenation of called abamectin ivermectin and 22,23-dihydroavermectin B1.

To fit the milbemycines include milbemycin B D, nemadectin and moxidectin.

According to another even more preferred embodiment of the invention proposed in the invention of solid medicines contain a combination of praziquantel, emodepside and one of the above macrocyclic lactones. In accordance with this variant implementation of the invention is even more preferred macrocyclic lactone is ivermectin.

Another group used according to the invention of active substances include analgesics, such as non-opioid analgesics or opioid analgesics. Suitable non-opioid analgesics include, for example, meloxicam, carprofen and Metamizole. Suitable opioid analgesics include, for example, bupremorfiny and Hairdryer-tanil.

An example of a preferred analgesic is Metamizole [N-methyl-N-(2,3-dimethyl-5-oxo-1-phenyl-3-pyrazolin-4-yl)aminoethanol-acid], called�I also dipyrone, which, as a rule, used in the form of the corresponding sodium salt. According to the invention can also be used with other pharmaceutically compatible salts. To be precise, Metamizole should be considered as a prodrug, which contains four main metabolite. Effective are two of the last, namely, first of all, 4-N-methylaminoethanol (4-MAA) and aminoantipyrine (4-AA).

In addition, active ingredients used in the proposed in the invention medicines are pharmacologically compatible derivatives of phosphonic acids, which typically involve organic compounds, particularly suitable as stimulators of metabolism and tonics for farm animals and Pets. Preferred examples of such active substances are long-known connection tadinfo and primarily butaphosphane (e.g., used in the preparation Catosal®), which, in particular, serve as additives to mineral substances (phosphorus).

The active substances depending on their structure can be in the form of stereoisomers or mixtures of stereoisomers, e.g. enantiomers or racemates. According to the invention can be used as a mixture of stereoisomers, pure stereoisomers.

In addition, when necessary�STI possible to use salts of active ingredients with pharmaceutically acceptable acids or bases, as well as solvates, especially the hydrates of the active ingredients or their salts.

According to a preferred embodiment of the invention under proposed in the invention medicines involve pills.

Proposed in the invention, the preparations contain prolong release of active ingredients in polymers, which involve swelling in water of the polymers. Since swelling in water of the polymers in the presence of water to form gels, such polymers may be described as gel-forming polymers. Examples of such polymers are chitosan, guar gum and polyvinyl acetate. According to the invention as a swelling in water of the polymers preferably used polyvinylpyrrolidone or their derivatives, and may also be used mixtures of polyvinylpyrrolidone and polyvinylpyrrolidone derivatives. However, particularly preferred is the use of polyvinylpyrrolidone.

Possible is also the use of polyvinylpyrrolidone in combination with other suitable polymers, and an example of such a combination may be the product Kollidon®SR BASF. This is about a mixture that contains subjected to spray-dried polyvinyl acetate (with a weighted mean molecular weight of about 450,000) and the soluble polyvinyl�raidon (Povidon K 30) in the ratio 8:2.

An example of a suitable derivative of polyvinylpyrrolidone is copovidone (e.g., Kollidon VA 64, BASF). This is of vinylpyrrolidone with vinyl acetate in the ratio 6:4.

Polyvinylpyrrolidone (povidone) are commercially available hydrophilic polymers suitable for use in solid drug with a slow release of the active substance. Commercially available are different grades of polyvinylpyrrolidone. Polyvinylpyrrolidone with a lower molecular weight is usually used as a binder for tablets. Polyvinylpyrrolidone swells in an aqueous medium and washed out. However, for example, in contrast to the simple esters of cellulose containing polyvinylpyrrolidone pills do not form a sticky gel layers. Made according to the present invention in vitro experiments also show the lack of bonding containing polyvinylpyrrolidone tablets in aqueous media. The use of multiple tablets is associated only with a low risk of any lumps in the intestinal tract of animals. The use of polyvinylpyrrolidone with different values of molecular weight allows, within certain limits, to vary the kinetics of active substance release.

Used according to the invention polyvinylpyrrolidone or production�s polyvinylpyrrolidone are preferably water-soluble polymers. The point is that, as a rule, is a linear unsewn polyvinylpyrrolidone or polyvinylpyrrolidone derivatives.

Index To polyvinylpyrrolidones or polyvinylpyrrolidone derivatives is usually at least 17.

Index To polyvinylpyrrolidones or polyvinylpyrrolidone derivatives depends on their viscosity and molecular weight and can be determined by known methods. In doubtful cases to Refine the indicator you can use to described in the European Pharmacopoeia data.

The preferred use of the subject polyvinylpyrrolidone and/or derivatives of polyvinylpyrrolidone with K values in the range of 17 to 90, particularly preferably from 25 to 90.

The finished product usually contains from 10 to 50 wt.%, preferably from 15 to 40 wt.%, particularly preferably 25 to 35 wt%. polyvinylpyrrolidone, polyvinylpyrrolidone derivative, or mixtures thereof.

According to a preferred embodiment, the use of polyvinylpyrrolidone and/or polyvinylpyrrolidone derivative with a small length of polymer chains and polyvinylpyrrolidone and/or polyvinylpyrrolidone derivative with longer polymer chains. This is especially effective to adjust the settings of the active substance release, pollicrystalline of short-chain polyvinylpyrrolidone or polyvinylpyrrolidone derivatives allows to provide a relatively rapid release of active substance, while the long-chain polyvinylpyrrolidone or polyvinylpyrrolidone derivatives cause a slower release of active substance. The weight ratio between long-chain and a short-chain polyvinylpyrrolidone or polyvinylpyrrolidone derivative can usually be varied in the range from 1:10 to only long-chain polyvinylpyrrolidone or polyvinylpyrrolidone derivative. The exact relationship of these components must be installed in accordance with the diffusion characteristics of the active substance. Water-soluble active substances, such as Metamizole, easily diffuse from the gel. In such a case, the suitable kinetics of active substance release can be achieved without the use of short-chain polyvinylpyrrolidone, respectively polyvinylpyrrolidone derivative, or in the presence of relatively small quantities of such polymers. Thus, according to a preferred embodiment of the invention the weight ratio between long-chain and a short-chain polyvinylpyrrolidone or polyvinylpyrrolidone derivative is in the range of at least from 5:1 to only one long-chain polyvinylpyrrolidone, preferably masso�nd the ratio of these components is at least 10:1.

The active substances of low solubility in water, such as emodepside or praziquantel, slowly diffuse out of the gel and released mainly as the destruction of the gel. To provide desired release kinetics of the active substance in such a case, it is recommended that the high content of short-chain polyvinylpyrrolidone or polyvinylpyrrolidone derivative. Thus, in accordance with another preferred embodiment the weight ratio between long-chain and a short-chain polyvinylpyrrolidone or polyvinylpyrrolidone derivative is in the range from 1:1 to 5:1, preferably from 2:1 to 4:1.

Index To short-chain polyvinylpyrrolidone or polyvinylpyrrolidone derivative is usually in the range of 17 to 40, preferably from 17 to 30, particularly preferably about 25.

Index To long-chain polyvinylpyrrolidone or polyvinylpyrrolidone derivative is usually about 40, preferably from 60 to 120, particularly preferably about 90.

For further information regarding the above polyvinylpyrrolidone, polyvinylpyrrolidone derivatives and some of their mixtures, can be found in the book by V. Buhler, "Kollidon, Polyvinyl-pyrrolidone for the pharmaceutical industry", 9th edition, BASF Pharma Ingredients, Germany, 2008.

�La controlling the speed of release of active substances proposed in the invention of drugs can be used water-soluble excipients, for example, such as polyethylene glycol, lactose (primarily in the form of lactose monohydrate), or polyhydric alcohols, in particular mannitol, sorbitol or xylitol, or mixtures of these excipients, which are usually optionally present in the preparations in an amount of from 1 to 20 wt.%, preferably from 5 to 15% of the mass.

An additional variation of the parameters of active substance release from the proposed in the invention of drugs can be done preferably by the introduction of disintegrating agents, such as starch, stitched natrocarbonatite, glycolate sodium starch and crosslinked polyvinylpyrrolidone (e.g., such as®Kollidon CL). The use of the above water-soluble excipients is not absolutely necessary. A preferred disintegrating agent is stitched natrocarbonatite, other preferred disintegrating agents include crosslinked povidone. In the case of disintegrating agents, their content in medicines is usually not more than 5% of the mass. and is preferably from 0.1 to 3 wt.%, particularly preferably from 0.5 to 1.5 wt%.

The combination of events described above allows to provide good reproducible bioavailability of the active substances at very n�significant risk of detection in the feces of animals nodestructurechanged or partially destructively tablets.

Solid medicines (e.g. tablets) may contain conventional fillers, such as carbonates, in particular calcium carbonate, bicarbonates, sodium chloride, aluminum oxides, silica gels, alumina, phosphates (primarily calcium phosphate) or organic fillers, in particular, lactose or microcrystalline cellulose. The filler is preferably used anhydrous calcium hydrophosphate. The preferred filler is microcrystalline cellulose. In addition, various fillers can be combined with each other. The total amount of filler (fillers) is usually from 5 to 80 wt.%, preferably from 10 to 70 wt.%, particularly preferably from 20 to 60 wt%.

Proposed in the invention of hard drugs in addition to one or more active substances and other of the above ingredients, if necessary, can also contain auxiliary substances, for example, lubricants for better sliding, in particular, colloidal silicon dioxide, e.g. Aerosil®, hydrogenated vegetable oil, stearic acid, talc or mixtures thereof, the amount which is usually from 0.1 to 2 wt.%, preferably from 0.5 to 1% of the mass.. the Content if required use of lubricants such as magnesium stearate, usually with�provide from 0.3 to 2 wt.%, preferably from 0.5 to 1.5 wt%.

According to a preferred embodiment of the invention to improve the taste add-smelling substances and/or flavorings.

Suitable additive to impart a smell of meat is dry powdered liver of cattle, poultry, sheep or swine, preferably poultry and pigs, as well as other substances that give medicinal smell. According to a preferred embodiment of the invention are suitable flavouring, respectively, giving the smell of the substance, which imply subjected to special processing of the mixture of proteins, fats and carbohydrates, primarily a product of Artificial Beef Flavor® company Pharma Chemie (Syracuse, Nebraska, USA). This is about the extract from pig's liver, which is added to other proteins. According to another preferred embodiment can also be used dry powdered liver. Taste, consequently giving the smell of the substances used in the proposed in the invention medicines at a level of from 1 to 40 wt.%, preferably from 5 to 30 wt.%, first of all, from 10 to 25 wt%. in terms of the total weight of the finished product. Percentage data are in terms of the finished product.

Proposed in the invention of PR�preparations can be made, for example, by mixing or granulating the above components and subsequent pressing of the obtained mixtures or granules into tablets. Preferred are methods of wet granulation. Giving smell, respectively, flavoring substances, disintegrating agents, external and internal lubricant, preferably admixed after the granulation, and the resulting mixture was then subjected to tableting.

Release of active substance from the proposed in the invention of drugs in vitro can be determined using the appropriate conventional apparatus in accordance with the specified in the USP methodology in immersion conditions. Thus under the conditions of immersion are usually meant to be used in pharmaceuticals test conditions under which the type and amount used for the active substance release to the environment has to be chosen so that it could be dissolved three times the amount of the respective active substance. The maximum amount of the specified medium is 900 ml. as the main component of this environment contains water, which improve the solubility, if necessary, adding a surfactant. The pH of the said medium by means of conventional buffers set at the level at which the suitable�existing active substance has maximum stability. The purpose of the present invention is to offer in the invention of drugs were capable of releasing in vitro during the interval from 1 to 6 hours, preferably from 1 to 5 hours, particularly preferably from 1.5 to 5 hours, at least 80%, preferably at least 85%, especially at least 90% active ingredient. The measurement is carried out at 37°C and the rotational speed of the stirrer 75 rpm In the case of the release of depsipeptides such as emodepside, containing depsipeptide preparations the pH used for the release environment set by the buffer (disodium hydrogen phosphate dehydrate/citric acid monohydrate) at level 3.0 and added 0.5% sodium lauryl sulfate. Volume of medium in the case of drugs, in a unit which contains up to 10 mg emodepside is 500 ml. When tested preparations with a higher content emodepside (e.g., tablets) must comply with the conditions of the dive. For example, when the content emodepside in unit drug equal to 30 mg, use 900 ml of medium.

The test contains Metamizole drugs in vitro is carried out in the following conditions: pH standard environment according to the USP monograph of 6.8 (phosphate buffer), the volume of the medium 900 ml.

Proposed in the invention medicines suitable �La treat people and also in the field of animal welfare and livestock for the treatment of farm and breeding animals, animals kept in zoos, as well as laboratory and experimental animals and Pets.

In this case, to agricultural and breeding animals include mammals, such as cows, horses, sheep, pigs, goats, camels, hippos, donkeys, rabbits, fallow deer, reindeer, fur-bearing animals such as mink, chinchilla or racoon, as well as poultry, such as chickens, geese, turkeys, ducks and ostriches.

For laboratory and experimental animals include mice, rats, Guinea pigs, hamsters, dogs and cats.

Pets include dogs and cats. Proposed in the invention medicines particularly preferably used for the treatment of cats and especially dogs.

According to a preferred embodiment of the invention medicines contain the above anthelmintic active ingredients. Such medicines are suitable for the destruction of pathogenic endoparasites occurring in humans, as well as in the field of animal welfare and livestock animals and breeding animals, animals kept in zoos, as well as in laboratory, experimental animals and Pets. Thus, depending on the type used�isoimage active substance such drugs are effective against pests in all or some stages of their development, and also against resistant species and species with normal sensitivity. The destruction of pathogenic endoparasites reduces the incidence and frequency of deaths, as well as, for example, to increase the productivity of the production of meat, milk, wool, hides, eggs, honey and so on due to the fact that the use of active substances allows more economical and just to contain the animals. To pathogenic endoparasites include tape worms, trematodes, nematodes and acanthocephala:

from the squad of pseudophyllidea, for example, Diphyllobothrium spp., Spirometra spp. Schistocephalus spp., Ligula spp., Bothridium spp. Diphlogonoporus spp.

from the squad of cyclophyllidea, for example, Mesocestoides spp. Anoplocephala spp. Paranoplocephala spp. Moniezia spp. Thysanosomsa spp. Thysaniezia spp. Avitellina spp. Stilesia spp. Cittotaenia spp. Andyra spp. Bertiella spp. Taenia spp. Echinococcus spp. Hydatigera spp. Davainea spp. Raillietina spp. Hymenolepis spp. Echinolepis spp. Echinocotyle spp. Diorchis spp. Dipylidium spp. Joyeuxiella spp. Diplopylidium spp.

from the subclass of the same sex, for example, Gyrodactylus spp., Dactylogyrus spp. Polystoma spp.

from the subclass bisexual, for example, Diplostomum spp. Posthodiplostomum spp. Schistosoma spp. Trichobilharzia spp. Ornithobilharzia spp. Austrobilharzia spp. Gigantobilharzia spp. Leucochloridium spp. Brachylaima spp. Echinostoma spp. Echinoparyphium spp., Echinochasmus spp. Hypoderaeum spp. Fasciola spp. Fasciolides spp. Fasciolopsis spp. Cyclocoelum spp. Typhlocoelum spp. Paramphistomum spp. Calicophoron spp, Cotylophoron spp. Gigantocotyle spp. Fischoederius spp. Gastrothylacus spp. Notocotylus spp. Catatropis spp. Plagiorchis spp. Prosthogonimus spp. Dicrocoelium spp. Eurytrema spp. Troglotrema spp. Paragonimus spp. Collyriclum spp. Nanophyetus spp. pisthorchis spp. Clonorchis spp. Metorchis spp. Heterophyes spp., Metagonimus spp.,

from the squad enabled, for example, Trichuris spp., Capillaria spp. Ttrichomosoides spp. The species Trichinella spp.

from the squad of Radimov, for example, Micronema spp., Strongyloides spp.,

from the squad strongylida, for example, Stronylus spp. Thodontophorus spp. Oesophagodontus spp. Trichonema spp., Gyalocephalus spp. Cylindropharynx spp. Poteriostomum spp. Cyclococercus spp. Cylicostephanus spp., Oesophagostomum spp. Chabertia spp., Stephanurus spp. Ancylostoma spp. Uncinaria spp. Bunostomum spp.,

Globocephalus spp. Syngamus spp. Cyathostoma spp. Metastrongylus spp. Dictyocaulus spp. Muellerius spp. protostrongylus spp. Neostrongylus spp. Cystocaulus spp. Pneumostrongylus spp. Spicocaulus spp. Elaphostrongylus spp.Parelaphostrongylus spp. Crenosoma spp. Paracrenosoma spp. Angiostrongylus spp. Aelurostrongylus spp. Filaroides spp. Parafilaroides spp.

Trichostrongylus spp. Haemonchus spp. Ostertagia spp. Marshallagia spp. Cooper/a spp. Nematodirus spp. Hyostrongylus spp. Obeliscoides spp. Amidostomum spp., Ollulanus spp.

from the squad pinworms, for example, Oxyuris spp., Enterobius spp. Passalurus spp., Syphacia spp. Aspiculuris spp. Heterakis spp.,

from the squad of ascarides, for example, Ascaris spp., Toxascaris spp. Toxocara spp. Parascaris spp., Anisakis spp. Ascaridia spp.,

from the order of spirurida, for example, Gnathostoma spp., Physaloptera spp. Thelazia spp. Gongylonema spp. Habronema spp. Parabronema spp. Draschia spp. Dracunculus spp.

from the squad filariid, for example, Stephanofilaria spp. Parafilaria spp. Setaria spp. Loa spp., Dirofilaria spp. Litomosoides spp. Brugia spp. Wuchereria spp., Onchocerca spp.

from the squad macroregion, for example, Filicollis spp., Moniliformis spp., Macracanthorhynchus spp., Prosthenorchis spp.

Especially preferred is the use proposed in the invention means against Toxocara cati, Toxascaris leonina, Ancylostoma tubaeforme, Dipylidium caninum, Taenia taeniaeformis � Echinococcus multilocularis.

If for the treatment of certain diseases other suitable well-known active substances according to the invention are suitable in principle are also medicines that contain relevant other active ingredients.

So, for example, to eliminate minor aches and pains, pain of moderate and severe pain, such as post-traumatic pain (caused by blunt force trauma or stretching of the knee), perioperative pain, postoperative pain, pain in the tumor area, osteoarthritis pain, theopathy, abdominal pain in the soft tissues or geriatric toothache, you can use analgesics, such as Metamizole.

Proposed in the invention medicines can be used both for prevention and therapeutic purposes.

Examples

A. formulation Examples

To prepare the following compositions are mixed with anhydrous calcium hydrogen phosphate, povidone 90 (and copovidone 64), the portion of the total quantity of 25 and povidone microcrystalline cellulose, then add emodepside and praziquantel. The resulting mixture granulated in the granulator fluidized bed at a temperature below 110°C, using an aqueous solution of another part of the povidone 25, and then dried. The granulate is sieved and mixed with UWC� - type addition of Artificial Beef Flavour, stitched natrocarbonatite, anhydrous colloidal silicon dioxide and magnesium stearate.

Obtained as described above, the material can be pressed into tablets.

Example 1

3,00 mgemodepside
15,00 mgpraziquantel
19,20 mganhydrous calcium hydrophosphate
37,80 mgmicrocrystalline cellulose
31,50 mgArtificial Beef Flavour (PC 0125, Pharma Chemie Inc., Syracuse, USA)
36,00 mgpovidone 90 (polyvinylpyrrolidone with K values 90)
12,90 mgpovidone 25 (polyvinylpyrrolidone with K values of 25)
0,90 mganhydrous colloidal silicon dioxide
1,20 mgcrosslinked sodium and carboxymethyl cellulose
1,50 mgmagnesium stearate

Example 2

10.00 mg emodepside

50,00 mgpraziquantel
64,00 mganhydrous calcium hydrophosphate
126,00 mgmicrocrystalline cellulose
105,00 mgArtificial Beef Flavour (PC 0125, Pharma Chemie Inc., Syracuse, USA)
120,00 mgpovidone 90 (polyvinylpyrrolidone with K values 90)
43,00 mgpovidone 25 (polyvinylpyrrolidone with K values of 25)
3,00 mganhydrous colloidal silicon dioxide
4,00 mgstitched natrocarbonatite
5,00 mgmagnesium stearate
Example 3
10.00 mgemodepside
50,00 mgpraziquantel
64,00 mganhydrous calcium hydrophosphate
126,00 mg microcrystalline cellulose
37,50 mgArtificial Beef Flavour (PC 0125, Pharma Chemie Inc., Syracuse, USA)
40,00 mgpovidone 90 (polyvinylpyrrolidone with K values 90)
42,00 mgpovidone 25 (polyvinylpyrrolidone with K values of 25)
2,00 mganhydrous colloidal silicon dioxide
4,00 mgstitched natrocarbonatite
3.75 mgmagnesium stearate

Example 4

500,00 mgMetamizole sodium
300,00 mgmicrocrystalline cellulose
300,00 mgpovidone 90 (polyvinylpyrrolidone with K values 90)
10.00 mganhydrous colloidal silicon dioxide
10.00 mgmagnesium stearate
Example 5
1000,00 mg Metamizole sodium
600,00 mgmicrocrystalline cellulose
600,00 mgpovidone 90 (polyvinylpyrrolidone with K values 90)
20,00 mganhydrous colloidal silicon dioxide
20,00 mgmagnesium stearate
278,00 mgpowdered dry liver
Example 6
10.00 mgemodepside
50,00 mgpraziquantel
64,00 mganhydrous calcium hydrophosphate
126,00 mgmicrocrystalline cellulose
105,00 mgArtificial Beef Flavour (PC 0125, Pharma Chemie Inc., Syracuse, USA)

90,00 mgpovidone 90 (polyvinylpyrrolidone with K values 90)
30,00 mgcopovidone 64 (Kollidon® VA 64, BASF, copolymer of vinyl-pyrrolidone with VI�racedata in the ratio 6:4)
43,00 mgpovidone 25 (polyvinylpyrrolidone with K values of 25)
3,00 mganhydrous colloidal silicon dioxide
4,00 mgstitched natrocarbonatite
5,00 mgmagnesium stearate
Example 7
10.00 mgemodepside
50,00 mgpraziquantel
64,00 mganhydrous calcium hydrophosphate
126,00 mgmicrocrystalline cellulose
105,00 mgArtificial Beef Flavour (PC 0125, Pharma Chemie Inc., Syracuse, USA)
30,00 mgpovidone 90 (polyvinylpyrrolidone with K values 90)
90,00 mgcopovidone 64 (Kollidon® VA 64, BASF, copolymer vinyl-
pyrrolidone with vinyl acetate in the ratio 6:4)
43,00 mgpovidone 25 (�polivinilpirrolidon with indicator 25)
3,00 mganhydrous colloidal silicon dioxide
4,00 mgcrosslinked sodium and carboxymethyl methyl cellulose
5,00 mgmagnesium stearate

Comparative example (the drug is not in accordance with the invention)

5,00 mgemodepside
50,00 mgpraziquantel
30,00 mganhydrous calcium hydrophosphate
63,00 mgmicrocrystalline cellulose
35,00 mgArtificial Beef Flavour
92,00 mghydroxypropyl cellulose-M (product NRS-M Japanese company Nisso)
1,00 mganhydrous colloidal silicon dioxide
3,00 mgmagnesium stearate.

According to the results of test carried out in accordance with the U.S. Pharmacopoeia, the release of 80% of the active ingredients in case of pills on DOS�ve of the formulation according to comparative example occurs within 12 hours. In the feces of subjects dogs detect partially disintegrating tablets, respectively remnants of the tablets. In the case of a few tablets observed them from sticking together and clumping.

The release of the active substance in vitro

The release of active substance from the proposed in the invention means in vitro evaluated by testing in accordance with USP, through immersion.

Fig.1 shows the test results of different tablets containing emodepside/praziquantel, and

small tablets based on the composition according to example 1

average tablet based on the compositions according to example 2

large tablets contain 30 mg emodepside and 150 mg praziquantel and have a composition similar to examples 1 and 2.

Test conditions: 37°C, 75 rpm, aqueous medium with a pH of 3.0 (disodium hydrogen phosphate dehydrate/monohydrate citric acid as a buffer), 0.5% sodium lauryl sulfate. For testing small and medium tablets use 500 ml of medium, while the major test of the tablets is carried out in 900 ml of medium.

As shown in Fig.1, a 90% release of active ingredients from all tablets occurs within the interval from 1 to 5 hours.

Examples of biological research

I. Pharmacokinetics�their research

The subjects of the drug gave the dogs on an empty stomach. At certain intervals of time performed a quantitative assessment of the level of active substances, active substances, respectively, in plasma.

Fig.2 shows the results of the test tablet-based composition of example 2. As shown in Fig.2 data show a very slow decrease in the concentration of praziquantel and especially emodepside in plasma.

II. The comparison contains Metamizole tablets with a market solution for intravenous metamizol application

Six dogs weighing from a 9.9 to 11.1 kg divided into two groups of three dogs. Each of the dogs the first group doing intravenous injection 500 mg drug market of metamizol Metapyrin®. Each of the dogs of the second group of Metamizole given orally in the form of the preparation of example 4, and the dosage is 500 mg. These drugs give a dog on an empty stomach.

Fig.3 shows the level of metamizol in plasma after application, and under the specified concentrations of metamizol [4-MAA+4-AA] the estimated mean value, which is the sum of the concentrations of both active main metabolite 4-MAA and 4-AA in the serum according to their molecular mass.

III. Plasma concentrations after oral administration of one or ductable of metamizol

Fig.4 shows Srednekanskaya of metamizol [4-MAA+4-AA] in serum after oral ingestion by dogs on an empty stomach one accordingly two tablets containing Metamizole in example 4. As shown in Fig.4, the plasma is quite well correlated with the dose taken.

1. Solid drug with a slow release of active substances, which contains:
a. the combination of praziquantel with emodepside as a pharmaceutically active substance in an effective amount,
b. 10 to 50 wt.% polyvinylpyrrolidone and/or polyvinylpyrrolidone derivative, which is a copolymer of vinylpyrrolidone with vinyl acetate in the ratio 6:4, and polyvinylpyrrolidone and/or polyvinylpyrrolidone derivative is a mixture
(i) one short-chain polyvinylpyrrolidone with K values from 17 to 30 and
(ii) polyvinylpyrrolidone or polyvinylpyrrolidone derivative with longer chains with the index To more than 40,
c. 5 to 80 wt.% at least one filler selected from the group comprising carbonates, bicarbonates, sodium chloride, aluminum oxides, silicic acid, alumina, phosphate, lactose, microcrystalline cellulose,
moreover, the amount of all components is 100 wt.%.

2. Solid medicament according to claim 1, further comprising dezintegriruetsja agent.

3. Solid medicament according to claim 2, containing desintegrates�th agent in an amount up to 5 wt.%.

4. Solid medicament according to claim 1, characterized in that the test performed as per the United States Pharmacopoeia at 37°C and stirring with a frequency of 75 rpm in a dive conditions, it releases 80% of depsipeptide as an active substance within the interval from 1 to 6 hours, and in the environmental quality of the release is used disodium hydrogen phosphate dehydrate/citric acid monohydrate buffer with pH value of 3 by addition of 0.5% sodium lauryl sulfate.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to an albendazole-based composition. The claimed composition consists of a substance of albendazole and arabinogalactane polysaccharide from Siberian larch or Gmelin with weight ratios of the components albendazole : arabinogalactane 1:5-20.

EFFECT: invention possesses the higher anti-opisthorchosis pharmaceutical activity than albendazole, and does not cause the toxic injury of hepatocytes.

3 cl, 7 dwg, 2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an amide of 2-(3-methyl-6-methoxy-7-ethoxy-3,4-dihydroisoquinolyl-1)-ethanoic acid hydrochloride of formula 1

EFFECT: obtaining a novel isoquinoline derivative, having anthelmintic activity.

1 tbl

FIELD: medicine.

SUBSTANCE: what is described is a gel containing structured nanovesicles - niosomes prepared from silicone compounds with enclosed albendazole, anthelmintic preparation.

EFFECT: invention enables extending the range of application of the anthelmintic preparations by reducing dyspeptic reactions that makes them applicable in both adults, and children suffering gastrointestinal diseases.

FIELD: agriculture.

SUBSTANCE: method of production of anthelmintic for group treatment of sheep with monieziasis is as follows: first, in the chemical reactor with anchor stirrer in polyethyleneglycol warmed to boiling the niclosamide is dissolved in the ratio of 4:1. Then, the resulting solution is added with beet molasses, lecithin, and sodium chloride in a ratio of 25:3:1:1 and mixed thoroughly. After that the mixture is added to oat flour - filler - in a ratio of 30:70 and mixed thoroughly until complete impregnation of the filler. The resulting mixture is subjected to granulation, the granule diameter is 3 mm. 1 kg of the agent contains 4% of active ingredient.

EFFECT: invention provides saving of the substance to prepare the agent, 5 times reduction of the therapeutic dose, decreased toxicity of the agent, increased bioavailability and improved eating of the agent, elimination of possible loss of active ingredient in dehelmintisation of animals.

3 ex

FIELD: medicine.

SUBSTANCE: declared invention refers to veterinary science and aims at treating the diseases caused by giardia. The declared drug as an active substance contains Nifurtimox.

EFFECT: using the declared drug is high effective in treating the diseases caused by giardia.

3 cl, 2 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to endocrinology, and deals with treatment of diabetes mellitus, complicated by accompanying diseases, in particular, by parasite invasions. For this purpose electro-activated water solutions of inorganic salts are introduced at the background of antihyperglycemic medications. On first 5 days solution of anolyte (EWS-A) with redox potential (RP) from +700 to +800 mV and with pH from 6.0 to 4.5, after which for 5 days introduced is catholyte solution (EWS-C) with RP from -400 to -600 mV and pH from 9.5 to 10.5; then for 10 days introduced are heated to +36°C - +37°C EWS-C and EWS-A are introduced with their alternation for 24 hours. In case of accompanying parasite invasion, EWS-A in combination with anti-parasitic vegetable medications in form of rectal microclysters for first 5 days of treatment is additionally introduced for first 5 days of treatment. EWS-C in combination with rectal microclysters with probiotic additives is introduced for the following 10 days. In case of detection of Opisthorchida, biltricide is introduced on the 15-th day in dose 75 mg/kg, and duodenal probing with anti-parasitic medication is carried out on the 16-th day. Starting with the 6-th day and to the completion of treatment (21-st day) fermented milk product "Narine" is administered in dose 1 tablespoon 3 times per day 30-40 minutes before meal.

EFFECT: mode of introducing electro-activated water solutions in complex with probiotics and anti-parasitic preparations provides efficient treatment of parasite invasions in combination with gradual normalisation of carbohydrate and lipid exchange in patients with diabetes mellitus.

2 cl, 2 ex, 4 tbl

FIELD: medicine.

SUBSTANCE: declared group of inventions refers to veterinary science and aims at controlling blood-sucking parasites and consuming parasites. The composition contains an antiparasitic effective subtoxic amount of imidacloprid in a single dose making 0.25 mg/kg to 30 mg/kg for oral delivery. Imidacloprid is the only antiparasitic being an ingredient of the composition. What is declared is using the above composition. The subtoxic amount of imidacloprid in a single dose makes 0.25 mg/kg to 30 mg/kg. The infestation is eliminated within 1-72 hours after administration of the single dose.

EFFECT: declared group of inventions provides effective elimination of blood sucking parasites and blood consuming parasites.

24 cl, 6 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: method for preparing a dry extract possessing an anti-opisthorchiasis action involving three extractions of the milled elevated portion of Centaurea plants of the family Asteraceae in ethanol; the extracts are combined and de-ethanolised; condensed residues are evaporated to dryness under certain conditions. Using the dry extract as the agent having the anti-opisthorchiasis action.

EFFECT: agent possesses the manifested anti-opisthorchiasis action.

2 cl, 7 tbl, 23 ex

FIELD: veterinary medicine.

SUBSTANCE: nocodazole is administered subcutaneously in an amount which does not cause formation of a connective tissue capsule around the medicinal product, 10 injections per day in a daily dose of 11-200 mg/kg with an interval of 3-4 days, in the points located on the dorsal and ventral surfaces of the animal body.

EFFECT: method is highly effective for treatment of cystic and alveolar larval echinococcosis and other tissue parasitic diseases of laboratory animals.

1 ex, 3 tbl

FIELD: veterinary medicine.

SUBSTANCE: method comprises the use of encapsulated fenbendazol. Sodium carboxymethyl cellulose is used as coating of the microcapsules. The microcapsules are obtained by the physico-chemical method of nonsolvent addition using two precipitators - carbinol and cyclohexanol. The ratio of core/polymer is 1:3. The preparation is given to animals at a dose of 22.5 mg/kg (15 mg/kg as active agent) as a single dose.

EFFECT: method is simple to use and is highly effective in the treatment of cattle with strongylatosis.

1 tbl

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel co-crystal, containing (rac)-tramadol HCl and celecoxib, with respective molecular ratio 1:1. Co-crystal can be used for treating pain, preferably acute pain, chronic pain, neuropathic pain, noticetive pain, minor and from severe to moderate pain, hyperalgesia, pain, associated with central sensitisation, allodynia or cancer pain, including diabetic neuropathy or diabetic peripheral neuropathy and osteoarthritis, fibromyalgia; rheumatois arthritis, ankylosing spondilitis, glenohumeral periarthritis or ischias. Co-crystal is characterised by peaks of powder X-ray diffraction, obtained with application of copper (CuKα1 1.54060 E), and irradiation and absorption bands of infrared spectra. Co-crystal has orthorhombic elementary cell with the following dimensions: a=11.0323 (7) E,b=18.1095 (12) E,c=17.3206 (12) E, as well as endothermic acute peak, corresponding to melt point, with start at 164°C.

EFFECT: invention also relates to method of obtaining co-crystal and based on it pharmaceutical composition.

8 cl, 9 dwg, 3 tbl, 1 ex

Csf-1r antibody // 2547586

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to immunology. There are presented an antibody and its antigen-binding fragment specifically binding human colony-stimulating factor-1 receptor (CSF-1R) characterised by sequences of complementary-determining regions (CDR). There are also disclosed a nucleic acid coding the antibody according to the invention or its antigen-binding fragment, a vector providing the expression of the antibody and its antigen-binding fragment, and a pharmaceutical composition applicable in treating the diseases associated with an inflammation or an autoimmunity, or cancer.

EFFECT: invention can find further application in diagnosing and therapy of the CSF-1 associated diseases.

23 cl, 18 dwg, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new aminotetraline derivatives of formula (I) and their physiologically tolerable salts. In formula

,

A means a benzene ring or a ring specified in a group consisting of a 5-merous ring

,

R means the group R1-W-A1-Q-Y-A2-X1-; R1 means hydrogen, C1-C6-alkyl, C3-C6-cycloalkyl-C1-C4-alkyl, halogenated C1-C6-alkyl, tri-(C1-C4-alkyl)-silyl-C1-C4-alkyl, C1-C6-alkoxy-C1-C4-alkyl, amino-C1-C4-alkyl, C3-C6-cycloalkyl, C2-C6-alkenyl, an optionally substituted phenyl, C1-C6-alkoxy, di-C1-C6-alkylamino, an optionally substituted 5 or 6-merous heterocyclyl containing 1-3 heteroatoms specified in nitrogen and/or oxygen or sulphur; W means a bond; A1 means a bond; Q means -S(O)2- or -C(O)-; Y means -NR9- or a bond; A2 means C1-C4-alkylene, or a bond; X1 means -O-, C1-C4-alkylene, C2-C4-alkynylene; R2 means hydrogen, halogen, or two radicals R2 together with the ring atom to which they are attached form a benzene ring; R3 means hydrogen. The other radical values are specified in the patent claim. The invention also refers to intermediate products for preparing the compounds of formula (I).

EFFECT: compounds possess the properties of glycine transporter inhibitors, particularly GlyT1 and can find application in treating neurological and psychiatric disorders, such as dementia, bipolar disorder, schizophrenia, etc or for managing pain related to glycerinergic or glutamatergic neurotransmission dysfunction.

20 cl, 2 tbl, 326 ex

FIELD: chemistry.

SUBSTANCE: medication includes 7.0-9.0 wt % of a dried thick fraction of a product of hazel dry sublimation, 0.025-0.033 wt % of hydrochloride anaprilin, 36.0-38.0 wt % of sodium hydrocarbonate, 24.5-25.5 wt % of boric acid, 12.0-16.0 wt % of phthalic acid, 5.5-7.5 wt % of sodium carboxymethylcellulose, 0.8-1.0 wt % of sodium dodecylsulphate, 0.45-0.55 wt % of calcium stearate and 5.5-10.8 wt % of glucose.

EFFECT: invention increases the therapeutic and preventive efficiency of treatment of postnatal endometritis in cows and cow-heifers.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to an agent for treating hemorrhoid, proctitis and other proctologic inflammations. The above agent represents a suppository 1,35 - 3,65 g containing diosmin 0,3 - 0,65 g, dexpanthenol 0,05 - 0,2 g, green tea extract 0,05 - 0,2 g as active substances, and emulsifier 0,0135 - 0,1825 g and fatty acid glycerides as additives.

EFFECT: agent provides the integrated antimicrobial, local analgesic, anti-inflammatory, wound healing and adaptogenic therapeutic action.

2 cl, 3 ex

FIELD: medicine.

SUBSTANCE: method for producing an anti-inflammatory glycolised polypeptide agent with the use of commercial sea urchin (Strongylocentrotus droebachiensis) waste. A method involves extracting sea urchin inners in ethanol, separating the extract in a separator or a centrifuge, evaporating it, filtering the concentrate, performing gel chromatography, separating a fraction having molecular weight 5.5-7.0 kDa and drying it in the certain environment. The produced agent possesses the pronounced anti-inflammatory action.

EFFECT: method enables improving purity of glycolised polypeptides.

3 cl, 4 tbl, 1 dwg, 4 ex

FIELD: medicine.

SUBSTANCE: method for producing a pigment complex of bisnaphthazarin for preventing inflammatory diseases, involving demineralising commercial sea urchins' crusts and needles in an organic acid solution, separating organic acid salts and protein, applying pigment solution on a chromatographic column, washing the column with diluted mineral acid and distilled water, eluting the pigment complex, combining fractions containing the pigments, removing ethanol, lyophilising concentrate in the certain environment. The complex of pigments bisnaphthazarins for preventing inflammatory diseases.

EFFECT: complex of pigments prepared by the above method is effective for preventing the inflammatory diseases.

3 cl, 2 dwg, 2 tbl, 4 ex

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to experimental medicine and gastroenterology, and can be used for the entero- and pancreatoprotective action of non-steroid anti-inflammatory preparations in simulating the gastric ulcer and/or pancreatitis experimentally. To this effect, the simulation is preceded by administering courses of Ketanov, Celebrex or Ketonal. The preparations are administered parenterally. A dose for the first three days is 2.5-3.1 mg/kg. A dose for the following three days is 1.5-2.4 mg/kg. That is followed by four days in a dose of 0.5-1.4 mg/kg with the therapeutic course repeated 1.5-2 months later. For the first three days of the repeated course, a dose of the preparation makes 0.7-2.0 mg/kg. A dose for the following three days makes 2.1-2.6 mg/kg. And for the final four days, a dose of the preparation makes 2.7-3.1 mg/kg.

EFFECT: method provides the effective entero- and pancreatoprotective action of the non-steroid anti-inflammatory preparations in simulating the gastric ulcer and/or pancreatitis experimentally with reducing the toxicity of the exposure.

3 ex

FIELD: medicine.

SUBSTANCE: invention refers to an anti-inflammatory and analgesic agent of 1,2-dihydro-1H-2-oxocinchoninic acid isopropylamide of formula

EFFECT: new agent possessing effective biological properties.

1 tbl

Fingolimod salts // 2543621

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new 2-amino-2-[2-(4-C2-20alkylphenyl)ethyl]propan-1,3-diol salts specified in tartrate, lactate benzoate, succinate, malonate, acetate and propionate in the crystalline form. Each of the above salts is characterised by powder X-ray pattern data. Compounds in the therapeutically effective amount can be used in treating autoimmune diseases.

EFFECT: crystalline salts of the present invention possess higher stability, better solubility, more convenient to store and handle.

11 cl, 7 dwg, 1 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to oral pharmaceutical composition in the form of a granulate produced without spheronisation. The composition contains 92-98 wt % of mesalazine or its pharmaceutically acceptable salt, 2-8 wt % of polyvinylpyrrolidone and an ethylcellulose coating, wherein the above coating weight relates to the above mesalazine weight as 0.3-1.5% and the ethylcellulose coating weight makes 0.11-0.15 mg/cm2. The granulate is packed in a sachet, a capsule or a blister. What is also described is a method for preparing a pharmaceutical composition.

EFFECT: ethylcellulose-coated mesalazine granulate combines a high drug load and a desired mesalazine release profile, namely, 5-25% of released mesalazine 15 min later, 30-70% of released mesalazine 90 min later and 75-100% of released mesalazine 240 min later.

10 cl, 1 ex

Up!