Ointment butadiona prepared on polyethylene oxide gel - 1500, which has anti-inflammatory action

 

(57) Abstract:

The invention relates to the field of pharmacy and for the preparation of soft medicinal forms, including ointments buttonboy. The invention lies in the fact that the proposed ointment contains butadiona 5.0 g, glycerol 10.0 g, trylon ± 0.1 g, sodium metabisulfite 0.1 g of polyethylene oxide gel-1500 to 100.0. The ointment is used as the basis of polyethylene oxide gel-1500. The invention provides a simplification of the production technology, as well as the cheaper product. table 1.

The invention relates to the field of pharmacy and applies the technology of cooking soft medicinal forms, namely ointment butadiona that have anti-inflammatory action.

Known ointment butadiona produced by the Chemical plant "Gedeon Richter" JSC (Hungary) based on the emulsion of the type oil-in-water content butadiona 5% under the name "Phenylbutazone ointment, which can be adopted for the prototype. To the disadvantage of the prototype, in our opinion, are fairly labour-intensive production technology ointment associated with the preparation of the emulsion base. The Russian pharmaceutical industry ointment butadiona produces.

Allienated-1500.

It is known that gels of polyethylene oxide have many positive qualities. The oxides dissolve in water and other polar solvents, easily washed off skin and clothes. They are resistant to the effects of light, temperature and moisture, which is insensitive to the introduction of electrolytes and pH variation in the environment, have a weak bactericidal action (Technology of dosage forms, edited by T. S. Kondratieva. -M, Medicine, 1991, T. 1, S. 289).

theoretical basis of the invention is the following.

The gel of polyethylene oxide-1500 (PEO) was developed at the Institute of Cytology and genetics CO RAS scientific company "BIOSIM" (patent of the Russian Federation 2026349) and issued by joint-stock company "Novosibirsk chemical concentrates plant", entitled "hydrogel GECO" TU M 9154-004-11821987-93. It is obtained from a 5% solution of polyethylene oxide-1500 using radiation technology. Gel PEO refers to practically non-toxic substances. In the study of acute and chronic toxicity of PEO gel in rats and mice found that intragastric, intraperitoneal injection, and when applied to the skin it does not affect the main indicators of the condition of the animals and the microstructure of the internal organs. Set practical besur the 4th class of hazard. It can serve as the basis for its use for medical purposes (Report on the experimental study of the toxic properties of polyethylene oxide gel-1500. Novosibirsk, 1993).

When studying the interaction butadiona with PEO-1500 found that the solubility of the drug is increased in 2 times. However, due to the fact that PEO-1500 cannot serve as ointment base, we used gel PEO-1500. The gel contains 93-95% of the water that allows you to dissolve in it medicinal substance, possessing at the same time sufficient structural viscosity and pronounced thixotropic properties.

When applying the gel into the skin loses moisture. To slow the loss of moisture in the composition to gel adds high-boiling liquid. When studying the influence of high-boiling liquids (glycerol, propylene glycol, dimethyl sulfoxide, silicone fluids, esters, PEO-400) found that the addition of the gel 10% of any of them significantly slows down moisture loss.

To select the optimal fluid were prepared ointments butadiona containing 10% glycerol or propylene glycol, polietilenglikolsuktsinata, dimethyl sulfoxide and 40% solution of silicone oil PMS-100 in dimethyl sulfoxide, respectively. Contents Butz cellophane membrane. The greatest rate of release was observed from ointments containing propylene glycol and glycerin. Therefore, for compositions we have chosen glycerol as the most available and cheap.

The study of the stability of ointments butadiona cooked on the gel PEO, were conducted according to the "Instructions for carrying out works for the purpose of determining the shelf life of medicines on the basis of the method of accelerated aging at elevated temperatures" --42-2-82. The number butadiona was determined by HPLC. In ointments that do not contain stabilizers, 6 months conditional storage was found only 42% butadiona. Of the investigated stabilizers were found the most effective mixture of trylon B and sodium metabisulfite, which helped extend the shelf life of ointment to two years and four months.

Conservation ointment us was not considered as the gel contains 0.5% sodium benzoate.

On the basis of this was composed of the following composition, g:

Phenylbutazone - 5,0

Glycerin - 10,0

Trilon B - 0,1

Sodium metabisulfite - 0,1

Gel PEO-1500 - Up to 100.0

Anti-inflammatory activity proposed composition was studied on the model of histamine-induced swelling of the paws of rats. In the e caused by the introduction under the aponeurosis of the hind legs of 0.1 ml of 0.1% solution of histamine dihydrochloride. We determined the effect of the ointment on the second phase of the inflammatory exudation. Edema was assessed ecometrics, the magnitude of swelling was determined from the change in volume of the paws in interest to the original volume, which was measured prior to the introduction of logogen, and after 0.5, 1, 2 and 3 hours. The effectiveness of the developed composition was compared with the effectiveness of the prototype - ointment butadiona 5% of the production company "Gedeon Richter". In parallel he studied anti-inflammatory activity basis - gel PEO-1500. Both the ointment and the gel was applied to 0.1 g for 0.5 hours prior to the introduction of logogen and after each measurement. The results presented in the table.

The effect of ointments butadiona 5% and PEO gel on histamine-induced swelling.

As follows from the presented data, the proposed ointment has the same anti-inflammatory activity, as the comparison drug. Therefore, the PEO gel can be used for the production of ointments butadiona.

Technology ointment: to knead the mixture butadiona, trylon B and sodium metabisulfite (particle size not exceeding 50 μm) add glycerine with constant stirring until a homogeneous mass. Then gradually add the gel PEO-1500 with constant stirring. It turns out the ointment b shall use as ointment bases gel PEO-1500.

Advantages of the proposed composition, while maintaining equivalent to prototype pharmacological action is:

1. simplifying the technological process of production of ointment, as it excludes the operation of emulsification;

2. reduction of the cost of the finished product.

Sources of information

1. Technology of medicinal forms: Textbook. 2 T. /T. S. Kondratyev, L. A. Ivanov, Y. I. Zelikson and others; Ed. by T. C. Kondratieva. - M.: Medicine, 1991.- So 1. - S. 289.

2. Report on the experimental study of the toxic properties of polyethylene oxide gel-1500. Novosibirsk, 1993.- C. 36.

3. "Hydrogel GECO" TU N 9154-004-11821987-93.

4. RF patent 2026349.

Ointment butadiona prepared on polyethylene oxide gel-1500, which has anti-inflammatory effect, containing phenylbutazone, Trilon B, metabisulfite, sodium, glycerin, characterized in that as the basis used gel of polyethylene oxide-1500 in the following ratio of components, g:

Phenylbutazone - 5,0

Glycerin - 10,0

Trilon B - 0,1

Sodium metabisulfite - 0,1

The gel of polyethylene oxide-1500 - Up to 100.0

 

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< / BR>
in which R1is phenyl, substituted cyclo(lower)alkyl, hydroxy(lower)alkyl, cyano, lower alkylenedioxy, carboxy, (lower alkoxy)carbonyl group, a lower alkanoyl, lower alkanoyloxy, lower alkoxy, phenoxy or carbamoyl, optionally substituted lower alkyl;

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< / BR>
where X is carbinieri, unsubstituted or substituted at the nitrogen atom by alkyl, aryl, heteroaryl or cyano, carbonyl, thiocarbonyl, sulfonyl, 1-nitroethene-2,2-diyl or 1,1-dicyano-Eten-2,2-diyl,

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the first of the residues Ra- Rdmeans A group-B-, in which A group of the formula

< / BR>
< / BR>
or

< / BR>
where pentostatin can be monogamist the remainder R25mono - or Disaese the remainder R26or monogamist the remainder R25and additionally monogamist the remainder R26and the substituents R25and R26that may be the same or different and have the meanings stated below, in one bancoestado 1 - 3 methine group may be replaced by a nitrogen atom or a group-CH= CH - may be replaced by a group-CO-NR1or one methine group may be replaced by nitrogen atom and one group-CH=CH - may be replaced by a group-CO-NR1-, where R1means a hydrogen atom or alkyl,

G1and G4- bond or methylene which may be mono - or Disaese the alkyl, aryl or heteroaryl, and the substituents may be the same or different,

G2- bond or methylene, substituted residues R7and R8,

G3communication, methyl nitrogen atom or Metin, unsubstituted or substituted by alkyl, aryl or heteroaryl,

R2is a hydrogen atom, alkyl, aryl or heteroaryl or hydroxyl or alkoxyl if at least one of the groups G2and G3doesn't mean the relationship,

R3is a hydrogen atom, alkyl, aryl or heteroaryl or R3together with R2form an oxygen atom, if at least one of the groups G2and G3doesn't mean the relationship,

R4and R14is a hydrogen atom, cycloalkyl with 3 to 7 carbon atoms, cycloalkyl with 3 to 7 carbon atoms in cycloalkyl parts, alkyl with 1 to 8 carbon atoms, alkenyl with 3 to 8 carbon atoms, which may not be linked to the nitrogen atom through the vinyl group, hydroxyalkyl, alkoxyalkyl, aminoalkyl, acylaminoalkyl, dialkylaminoalkyl, cianelli, carboxyethyl, alkoxycarbonylmethyl, aminocarbonylmethyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl, arylalkyl, heteroallyl, alkoxycarbonyl, allmediascotland, formyl, acetyl, TRIFLUOROACETYL, allyloxycarbonyl, amidino or R11CO-0-(R12CR13)-O-CO-, where R11is alkyl with 1 to 8 carbon atoms, cycloalkyl with 5 to 7 carbon atoms, aryl or arylalkyl, R12is a hydrogen atom, alkyl, cycloalkyl with sweetlenny alkylen 2 - 4 carbon atoms or methylene, if G2doesn't mean the relationship,

R5is a hydrogen atom, alkyl, aryl or heteroaryl or hydroxyl or alkoxyl, if G1no means of communication, or R4together with R5mean an additional bond, if G1means of communication,

R6is a hydrogen atom, alkyl, aryl or heteroaryl or a chlorine atom, a hydroxyl, methoxyl, amino, alkylamino or dialkylamino, if G1means linking and R4together with R5mean an additional bond, or R6together with R5mean oxygen atom, if G1doesn't mean the relationship,

R7is a hydrogen atom, alkyl, aryl or heteroaryl,

R8is a hydrogen atom, alkyl, aryl or heteroaryl or R8together with R4mean the unbranched alkylene with 2 to 5 carbon atoms,

R9is a hydrogen atom, alkyl, aryl or heteroaryl or hydroxyl or alkoxyl, if G2doesn't mean the relationship,

R10is a hydrogen atom, alkyl, aryl or heteroaryl or R10together with R4mean the unbranched alkylene with 2 to 4 carbon atoms,

R15is a hydrogen atom or chlorine, alkyl, aryl, heteroaryl, hydroxyl, methoxyl, amino, alkylamino or dialkylamino,

R16- foelkel 1 8 carbon atoms, alkenyl with 3 to 8 carbon atoms, which may not be linked to the nitrogen atom through the vinyl group, hydroxyalkyl, alkoxyalkyl, aminoalkyl, acylaminoalkyl, dialkylaminoalkyl, cianelli, carboxyethyl, alkoxycarbonylmethyl, aminocarbonylmethyl, N-alkylaminocarbonyl, N,N-dialkylaminoalkyl or arylalkyl,

R17is a hydrogen atom or alkyl, or R16together with R17mean an additional bond, if G4means of communication,

R18is a hydrogen atom, alkyl or fluorine atom, chlorine or bromine, hydroxyl, methoxyl, amino, alkylamino or dialkylamino, if G4means linking and R16and R17together denote an additional bond,

n is the number 1 or 2,

In - line, alkylen, albaniles, Allen, peridinin, pyrimidinyl, personalen or pyridazinyl, in which one or two groups-CH=N - can be replaced by a group-CO-NH - and one of the nitrogen atoms may be associated with the remainder of A connection instead of a hydrogen atom, and these heterocyclic groups may be optionally substituted by one or two alkyl groups, cycloalkyl with 4 to 7 carbon atoms, unsubstituted or substituted by one or two alkyl groups, unsubstituted or RC="http://www.fips.ru/fullimg2/rupat3/19993/003.dwl/2126002-6t.gif" ALIGN="ABSMIDDLE">replaced by a nitrogen atom, and, in addition, in the above mentioned 5 - to 7-membered rings, one adjacent to the nitrogen atom of the methylene group may be replaced by carbonyl, the second of the residues Ra- Rdmeans a group of the formula

F - E - D-,

where D is alkylene with 1 to 6 carbon atoms in which one methylene group may be replaced by oxygen atom or sulfur, sulfinil, sulfonium or the group-NR19-, where R19means a hydrogen atom, alkyl, alkylaryl, alkylsulfonyl, arylcarbamoyl or arylsulfonyl, or in which one ethylene group may be replaced by a group-CO-NR20- or-NR20-CO-, where R20means a hydrogen atom or alkyl, albaniles with 2 to 6 carbon atoms, Allen, peridinin, pyrimidinyl, personalen or pyridazinyl, in which one or two groups-CH=N - can be replaced by a group-CO-NH - and one of the nitrogen atoms, together with the hydrogen atom may also be linked with the rest of E, if the latter does not mean the connection or not connected via a heteroatom or a carbonyl with the rest of D, and these heterocyclic groups may be optionally substituted by one or two alkyl groups, indaniel, naftilan, 1,2,3,4-tetrahydronaphthalen or benzoguanamine, in which one of the be substituted by one or two alkyl groups, and the aromatic ring may be substituted by fluorine atom, chlorine, bromine or iodine, alkyl, trifluoromethyl, hydroxyl, alkoxyl, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl or cyano, cycloalkyl with 4 to 7 carbon atoms, unsubstituted or substituted by one or two alkyl groups, unsubstituted or substituted by one or two alkyl groups cycloalkyl with 5 to 7 carbon atoms, in which one groupreplaced by a nitrogen atom, and, in addition, in the above mentioned 5 - to 7-membered rings, one adjacent to the nitrogen atom of the methylene group may be replaced by carbonyl, unsubstituted or substituted by one or two alkyl groups piperazinyl in which one adjacent to the nitrogen atom of the methylene group may be replaced by a carbonyl, or alkilenkarbonatov with the total number of carbon atoms 2-6, if E is a cyclic aminogroup, and a carbonyl linked to a nitrogen atom of a cyclic aminogroup group E, or a link, if E does not mean the relationship,

E - communication, alkylene with 1 to 6 carbon atoms which may be substituted by one or two alkyl groups with 1 to 8 carbon atoms, alkenyl or quinil with 2 to 4 carbon atoms, hydroxyl, is POI with the total number of carbon atoms of 2 10, the group HNR21- or N-alkyl-NR21-, where R21means alkylsulphonyl or alkylsulfonyl with 1 to 8 carbon atoms in the alkyl part, allyloxycarbonyl with the total number of carbon atoms 2 and 5 cycloalkylcarbonyl or cycloalkylcarbonyl with 5 to 7 carbon atoms in cycloalkyl part, arylalkylamines, arylalkylamines, arylethoxysilanes, arylcarbamoyl or arylsulfonyl, albaniles with 2 to 6 carbon atoms, Allen, peridinin, pyrimidinyl, personalen or pyridazinyl, unsubstituted or substituted by one or two alkyl groups, unsubstituted or substituted by one or two alkyl groups cycloalkyl with 5 to 7 carbon atoms, in which one groupreplaced by a nitrogen atom linked to the carbon atom of the residue D, cycloalkyl with 4 to 7 carbon atoms in cycloalkanones part, unsubstituted or substituted by one or two alkyl groups with 1 to 8 carbon atoms, alkenyl or quinil with 2 to 4 carbon atoms, hydroxyl, amino, aryl, heteroaryl, alkoxyl or alkylamino with 1 to 8 carbon atoms, dialkylamino with the total number of carbon atoms of 2 to 10, a group HNR21- or N-alkyl-NR21-, where R2119-, -NR20-CO - or-CO-NR20-, where R19and R20have the above meanings, with alkylene may be optionally substituted by one or two alkyl groups with 1 to 8 carbon atoms, alkenyl or quinil with 2 to 4 carbon atoms, hydroxyl, amino, aryl, heteroaryl, alkoxyl or alkylamino with 1 to 8 carbon atoms, dialkylamino with the total number of carbon atoms of 2 to 10, group-HNR21- or N-alkyl-NR21where R21have the above significance, with an additional heteroatom substituent heteroatom is separated from the remainder of W by at least two carbon atoms, if D does not mean the relationship,

F - carbonyl, substituted by hydroxyl, alkoxyl with 1 to 8 carbon atoms, arialcategory or group R22O-, where R22means cycloalkyl with 4 to 8 carbon atoms and cycloalkyl with 3 to 8 carbon atoms in cycloalkyl part, in which cycloalkyl part may be substituted by alkyl, alkoxyl or dialkylamino, or alkyl and 1 to 3 methyl groups, with one methylene group in the 4 - to 8-membered cycloalkyl part may be replaced by oxygen atom or alkylaminocarbonyl, benzocyclobutene the PA R23CO-O-CHR24-O-CO-, where R23means alkyl or alkoxy with 1 to 8 carbon atoms, cycloalkyl with 5 to 7 carbon atoms, cycloalkyl with 5 to 7 carbon atoms in cycloalkyl parts, aryl, aryloxy, arylalkyl or Allakaket and R24is a hydrogen atom or alkyl,

the shortest distance between the residue of F and located at a maximum distance from the rest F the nitrogen atom of the group A-B - is at least 11 links,

the third of the residues Ra- Rdmeans a hydrogen atom, alkyl, perfluoroalkyl, alkoxy, alkylsulfanyl, alkylsulfonyl, alkylsulfonyl, amino, alkylamino, dialkylamino, aryl, heteroaryl or arylalkyl,

the fourth of the residue Ra- Rdmeans a hydrogen atom, alkyl or aryl, and if nothing else is mentioned,

under the above term "aryl" is to be understood phenyl, which can be monogamist the remainder R25mono-, di - or triamese the remainder R26or monogamist the remainder R25and additionally mono - or Disaese the remainder R26and the substituents may be the same or different, R25means cyano, carboxyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, alkoxycarbonyl, alkylboron, the Mino, alkylamino, dialkylamino, alkylcarboxylic, phenylalkylamine, phenylcarbonylamino, alkylsulfonyl, phenylalkylamine, phenylcarbonylamino, N-alkyl-alkylcarboxylic, N-alkyl-phenylalaninamide, N-alkyl-phenylcarbonylamino, N-alkyl-alkylsulfonyl, N-alkyl-phenylalaninamide, N-alkyl-phenylcarbonylamino, aminosulfonyl, alkylaminocarbonyl or dialkylaminoalkyl, R26- alkyl, hydroxyl or alkoxy, fluorine atom, chlorine, bromine or iodine, and two residue R26if they are linked to adjacent carbon atoms, may also be alkylene with 3 to 6 carbon atoms, 1,3-butadiene-1,4-deelen or methylendioxy group

under the above term "Allen" should be understood phenylene, which can be monogamist the remainder R25mono - or Disaese the remainder R26or monogamist the remainder R25and additionally monogamist the remainder R26and the substituents may be the same or different and have the above values,

under the above term "heteroaryl" should read 5-membered heteroaromatic ring containing one atom of oxygen, sulfur or nitrogen, one atom of nitrogen and one atom of oxygen, sulfur is certain heteroaromatic ring, in which one or two of the groups-CH= N - can be replaced by a group-CO-NR20where R20has the above value, the heteroaromatic ring can be substituted by one or two alkyl groups or by a fluorine atom, chlorine, bromine or iodine, hydroxyl or alkoxyl in the carbon skeleton,

and, if nothing else is mentioned, the above alkyl, alkylene or CNS groups can contain 1 to 4 carbon atoms and each of the carbon atoms in the above alkilinity and cycloalkenes groups associated at least one heteroatom,

mixtures of their isomers, or individual isomers or salts

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