Pharmaceutical composition having spasmolytic activity, its preparation

 

(57) Abstract:

The invention relates to chemical-pharmaceutical industry, namely the creation of a pharmaceutical composition having spasmolytic activity. The proposed structure includes drotaverine hydrochloride, milk sugar (lactose), starch potato, crosspovidone (kollidon CL), talc, calcium stearate. Method for obtaining a pharmaceutical composition, which consists in the fact that the mixture of drotaverine hydrochloride, potato starch, lactose hydrate 3% starch paste, granularit, dried, re-passed through the granulator, dry granulate is mixed with crosspovidone, calcium stearate and talc, tabletirujut. The method provides uniform mixing of the components, optimal bioavailability of the active substance, and also provides for the disposal of waste. The proposed arrangement meets the requirements of the State Pharmacopoeia XI, stable during prolonged storage, has improved organoleptic properties. The combination of all excipients provides a high rate of dissolution, in which the optimal profile visvobodi is the itsindustry, namely, to create a pharmaceutical drug that has antispasmodic effect.

There is currently a wide range of antispasmodic drugs, one of the representatives is drotaverine hydrochloride (no-Spa) - 1-(3,4-Diethoxyaniline)-6,7-diethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride. On pharmacological properties of drotaverine is very close to that of papaverine, but has a more pronounced and more prolonged pharmacological effect. Applied with stomach cramps and bowel, spastic constipation, stroke and chronic urolithiasis (colic, cholecystitis, cholangitis. Can also be used as an auxiliary agent in hypertensive crises, headache (Mashkovsky M. D. Medicines. M , 2000, volume 1, page 397).

Drotaverine hydrochloride, like most substances, medicines, has no ability to direct pelletizing. Therefore, to create stable for quite a long time, meet pharmacopoeial requirements of the dosage form is necessary to introduce auxiliary substances in quantities defined pharmaceutical and therapeutic usefulness. the second derivative of isoquinoline, a structural analogue of drotaverine and excipients in the following ratio, wt.%:

1-(3,4-Diethoxybenzoic)-6,7-diethoxy-3,4-dihydro-izohinolinove-7-acetate monohydrate - 27,78

Calcium citrate - 65,56

Crystalline cellulose - 5,56

Magnesium stearate - 1,11

The drug has antispasmodic effect. The disadvantages of the above composition should include a high content of filler is calcium citrate (65,56%). Excessive increase in the content of citrate may cause changes in pH when dissolved. In addition, the content of magnesium stearate exceeds the allowable State Pharmacopoeia XI limit of 1% (the State Pharmacopoeia of the USSR XI, editions 1, 2, M, 1998).

In the European patent EP 0067711, B1, 22.12.82, Chinoin Gyogyszler es Vegyeszet, A 61 K 31/47 presents tablets a drug that has antispasmodic effect and containing as active ingredient a derivative of isoquinoline and targeted supplements. The product has the following composition, wt.%:

6,7-Diethoxy-1-(4-ethoxy-3-hydroxy-benzyl)-3,4 - dihydro-isoquinoline - 40,01

Crystalline cellulose - to 18.01

Lactose - 30,61

Polyvinylpyrrolidone - 7,20

Pyrosulfite sodium - 0,20

The connection CTSA in the following.

The mixture is dried powders 6,7-diethoxy-1-(4-ethoxy-3-hydroxy-benzyl)-3,4-dihydro-isoquinoline, cellulose and lactose hydrate aqueous-alcoholic suspension (using 96% ethanol) containing polyvinylpyrrolidone, pyrosulfite sodium and stearic acid at a temperature of 40oWith, granularit, dried. Next, perform a dry granulating the obtained granules optivault mixture containing colloidal compound of silicon and magnesium stearate and pressed into tablets.

The disadvantages of the presented composition should include a high content of stearate (3%), does not meet the requirements of the State Pharmacopoeia XI. The increase in the content of stearate in comparison with regulated may cause irritation of the gastric mucosa. The disadvantages of the method of obtaining the drug should include the use of ethanol in the production process. Thus, the use of flammable substances requires compliance with certain safety and possibly additional equipment.

Closest to the proposed invention is a preformed drug spasmolytic actions, disclosed in WO 9904822, 04.02.99, Seres Istvan et all, A 61 K 47/48. The drug contains, wt%:
consistent starch - 12,11

Polyvinylpyrrolidone - 2,41

Lactose - 24,21

Microcrystalline cellulose - 21,79

The method of obtaining the drug is as follows.

The powders are mixed, granularit and pressed into tablets.

Given the drug has improved organoleptic properties due to the use of Sheremetevo derivative of drotaverine, which is obtained by the interaction of drotaverine main with alcoholic solution of sabarimala. However, a significant drawback of the proposed composition is the use of hard substances Sheremetevo derivative of drotaverine. Getting the same Sheremetevo derivative of drotaverine involves the introduction of additional stages in the production technology and the use of additional substances. In addition, the content of stearate in the product exceeds the allowable State Pharmacopoeia XI limit of 1% (in the above structure - 1,21%).

The objective of the invention is to develop a pharmaceutical composition having antispasmodic action that meets pharmacopoeial requirements, stable during storage and has improved organoleptic properties. In another AU is developing ways of obtaining this pharmaceutical compositions with optimal bioavailability of the active component.

This object is achieved in that the proposed pharmaceutical composition contains the available RF chloride-hydrogen salt of drotaverine (drotaverine hydrochloride), which has expressed a myotropic antispasmodic effect. As auxiliary substances it contains milk sugar (lactose), potato starch, calcium stearate, talc, crosspovidone (kollidon CL) in the following ratio, wt.%:

Drotaverine hydrochloride - 26,4285-30,7143

Milk sugar (lactose) - 53,6072-59,2500

Potato starch - 12,4286-14,5125

Crosspovidone (kollidon CL) - 0,45-0,55

Talc - 0,45-0,55

Calcium stearate - 0,45-0,55

Specially selected combination of components (a high content of lactose - 59,2500 wt. %) provides superior organoleptic properties of the composition, and also contributes to a better release of the active substance from the dosage form.

Introduction starch having lubricating properties, can reduce the content of other anti-friction additives, talc and calcium stearate to values not exceeding the allowed Pharmacopoeia GF XI (3 wt.% and 1 wt.%).

The combination of all excipients provides high pokazatel obojdetsya not less than 90% of drotaverine hydrochloride.

The pharmaceutical composition is in tablet form that allows for maximum adaptability subsequent packaging and precision dosing of the active substance.

The obtained pharmaceutical composition complies with the requirements of the State Pharmacopoeia XI, stable during prolonged storage.

Feature of the method of producing the drug in comparison with the counterparts is the use of crosspovidone (kollidon CL) in the composition apadravya mixture, as well as the introduction of apadravya mixture milled substandard tablets. Thus, the method provides for the disposal of waste. For the most uniform distribution of the binding agent (starch) it is appropriate to introduce it in the form of a 3%-aqueous paste. Starch paste is environmentally friendly and safe raw material.

The proposed method provides optimal bioavailability of the active substance. In more detail, the method of obtaining the drug discussed in example 2.

Example 1. An example of a composition having antispasmodic effect, mass. %:

Drotaverine hydrochloride - 28,5714

Lactose - 56,4286

Potato starch - 13,5

Crosbie, have antispasmodic effect.

1. Preparation of raw materials.

1.1. Drying of starch.

In the dryer bin school-154 download 59,15 kg of starch with moisture content of 18% and dried at (505)oC for (4,50,5) h to a moisture content of 5%. Then dry the starch is cooled and sent to the stage of prosave. After drying the starch to keep no more than 3 days.

The calcined talc for 3-4 h at (1155)oC.

1.2. The grinding of drotaverine hydrochloride.

Coarse powder of drotaverine hydrochloride grind at the mill GF-149 into a fine powder with a particle size of 0.1 to 0.2 mm and is passed to the stage of prosave.

1.3. Preparation of 3% starch paste.

In reactor R-155 pour 66 liters of water and bring to a boil (955)oC under stirring, add a suspension consisting of 2,13 kg of starch are 2.87 liters of water. The mixture is stirred for 10 min and cooled to (255)oC.

1.4. Sifting raw materials.

Sifting of potato starch, lactose, calcium stearate, talc, drotaverine hydrochloride are on the sieve GF-152, 153 hole diameter of 0.2 mm are Sifting through a sieve of 32 or 38).

All materials used in the production of raw materials: drotaverine hydrochloride - 6,visivolt on the scales.

In the mixer GF-156 download sequentially: drotaverine hydrochloride, potato starch, lactose. The mixture is stirred in a high speed mixer for 3-5 minutes until a homogeneous mixture and then moisturize with stirring 3% starch paste, the mixture is stirred in a high speed mixer for 3-5 minutes until evenly moistened mass.

The wetted mass is discharged from the mixer GF-156 and passed through a granulator GF-157 hole diameter drum 1.5 mm, after which the mixture is spread out on trays GF-2 layer (1.5 to 2.0) cm and is passed to the drying operation.

3. Drying and dry granulation.

The wet granulate is dried in a tray dryer SL-4-18 school-154 if (655)oC for 2,5-4,0 h, periodically mixing the granulate with a wooden spoon until a residual moisture content (2,250,25)%.

Drying of the product by submitting a fan PU-1 camera dryer warmed up (705)oC air and exhaust its exhaust fan-3.

After drying, the dried mass is passed through a granulator GF-157 with the diameter of the drum 1 mm and collect in containers GF-151. The dry granulate is passed through the receiving tablemats and tableting.

4. Prigot is at; 0,112 kg - crosspovidone, 0,105 kg milled in GF-157 substandard tablet, everything is stirred for 10-15 minutes Then add 0,112 kg of calcium stearate and 0,112 kg of talc powder, all mixed for 10-15 minutes and discharged into the tank GF-151 (dusting).

The tabletting mixture kumajirou for 15 min in the boiler GF-161 and pass on stage tableting.

5. Tableting and rejection.

Tableting is performed on a rotary press RTM-41 GF-162 with a diameter of 9 mm punches, with beveled edges and scored. Tablets of drotaverine hydrochloride should take the form of a face with beveled edges and scored, solid edge, smooth and uniform surface. Average weight from 0,266 to 0,294 g, deviations in the weight of individual tablets of 7.5%. Tablets should possess sufficient strength mechanical influences.

7. Stage of packing.

1. Pharmaceutical composition having spasmolytic activity, in the form of tablets containing drotaverine and target additives, characterized in that it contains drotaverine in the form of its hydrochloric salt, and the target additives, lactose, potato starch, crosspovidone, talc, calcium stearate in the following ratio of components is -14,5125

Crosspovidone - 0,45-0,55

Talc - 0,45-0,55

Calcium stearate - 0,45-0,55

2. A method of obtaining a pharmaceutical composition having spasmolytic activity, characterized in that the mixture of drotaverine hydrochloride, potato starch, lactose hydrate 3% starch paste, granularit, dried, re-passed through the granulator, dry granulate optivault the crosspovidone, calcium stearate and talc, tabletirujut.

3. The method according to p. 2, characterized in that for dusting optional add ground substandard tablets.

 

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FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of benzimidazole represented by the following formula (I) or its salt:

wherein R1 represents (lower)-alkyl group; R2 represents aromatic (lower)-alkyl group that can be substituted with one or more groups taken among halogen atom, alkyl group, halogen-(lower)-alkyl group, nitro-group, aromatic group, aromatic (lower)-alkoxy-group, (lower)-cycloalkyloxy-(lower)-alkyl group, aromatic (lower)-alkyl group, aromatic (lower)-alkenyl group, aromatic (lower)-alkynyl group, aromatic oxy-(lower)-alkyl group, (lower)-cycloalkyl-(lower)-alkoxy-group, alkenyl group, (lower)-alkoxy-group, (lower)-alkylthio-group and (lower)-alkanesulfonylcarbamoyl group; R3 represents alkyl group, hydroxy-(lower)-alkyl group, alkenyl group, aromatic group, halogenated aromatic group, (lower)-alkyl aromatic group, (lower)-alkenyl aromatic group or aromatic (lower)-alkenyl group; -X- represents cross-linking group represented by one of the following formulas: (II) , (III) , (IV) , (V) . Also, invention relates to pharmaceutical compositions eliciting activity that reduces blood glucose level based on this compound. Invention provides preparing new compounds and pharmaceutical compositions based on thereof used for prophylaxis and treatment of damaged tolerance to glucose, diabetes mellitus, insulin-resistance syndrome, vascular failures syndrome, hyperlipidemia and cardiovascular disorders.

EFFECT: valuable medicinal properties of compounds and compositions.

16 cl, 1 tbl, 86 ex

FIELD: medicinal industry.

SUBSTANCE: the present innovation deals with manufacturing medicinal preparation containing drotaverin hydrochloride to be applied for interrupting spasms of smooth musculature. Mass for tableting should be prepared due to mixing the powder of drotaverin hydrochloride with that of dyed granulate at the ratio of 1:3 to 2:1. One should obtain the dyed granulate by moisturizing inert pharmaceutical filler with binder's solution dyed with quinoline yellow dyestuff. Then comes drying up to 0.1-2.5% followed by granulation and tableting. The innovation enables to obtain tablets of drotaverin hydrochloride upon industrial equipment at its degradability being below 15 min, being stable during manufacturing and at storage. Quality of tablets meets all the requirements of pharmacopoeic article.

EFFECT: higher efficiency of manufacturing.

2 cl, 4 ex, 3 tbl

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EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

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13 cl, 7 tbl, 75 ex

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eliciting physiological activity, in particular, capacity to inhibit activity of protein kinase, and also to intermediate compounds for their preparing and to the focused library, for search compound-leaders and medicinal candidates obtaining on the basis of screening combinatory libraries. In compounds of the general formula (1) R1 represents hydrogen atom or electrophilic substitute; R2 represents hydrogen atom or inert substitute; R3 represents optionally substituted hydroxyl group, optionally substituted amino-group and optionally substituted azaheterocycle; R4 represents optionally substituted amino-group and optionally substituted azaheterocycle. Also, invention relates to compounds of the general formula (1.1):

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and (1.3):

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