LT4899B - Antiarrythmic drug - Google Patents

Abstract

The present invention is a medicament for use as a medicament for the treatment of arrhythmia containing (2-butyl-3-benzofuranyl) [4- [2- (diethylamino) ethoxy] -3,5-diodophenyl] methanone hydrochloride, the common name of which is amiodarone. for the treatment of arrhythmia, tachycardia, extrasystole, heart rhythm disorders and prevention of relapse. @ The drug is in the form of tablets. Amiodarone Hydrochloride and Corn Starch Starch Sodium Glucolate are present in a ratio of 2.3: 1, and the components in each tablet are: @nuo 100 to 300 mg amiodarone hydrochloride, 40 to 90 mg corn starch, 10 to 30 mg starch sodium glucolate, 6 to 18 mg copolyvidone VA64, 15 to 35 mg mannitol SD200, 0.5 to 35 mg colloidal silicon dioxide, 6 to 15 mg talc and 1 to 5 mg magnesium stearate. the composition is simpler, and the selected additives guarantee very good physico-mechanical properties, improved in vitro dissolution of the active substance and therapeutic plasma levels confirmed by bioequivalent tests.

Description

The present invention is an antiarrhythmic drug containing (2-butyl-3-benzofuranyl) [4- [2- (diethylamino) ethoxy] -3,5-diiodophenyl] methanone hydrochloride, commonly called amiodarone, used as a medicine in medicine. arrhythmia, tachycardia, extrasystole, cardiac arrhythmia and prevention of relapse.

An antiarrhythmic drug containing amiodarone hydrochloride is available, and the active ingredient is formulated as a pre-formulated dry granulate.

For this purpose, amiodarone hydrochloride is mixed with 40% by weight of microcrystalline cellulose (Avicei PH 102) and 64% by weight of water. A wet mass is obtained which is dried in a vortex dryer and the resulting dry granulate (90.25g) is mixed with 1.45g microcrystalline cellulose, 5.34g low-substituted hydroxypropylcellulose, 2.00g dye, 0.16g colloidal silica gel and 0.80g magnesium. stearate. The composition of the resulting tablets and the technology for their manufacture are quite complex (see EP330284).

Arrhythmia is known with amiodarone hydrochloride, which contains the following components in a 500 mg tablet: 200 mg amiodarone hydrochloride, 125 mg lactose, 130.5 mg wheat starch, 20 mg polyvinylpyrrolidone, 10 mg alginic acid, 1.5 mg colloidal silica, 3 mg magnesium stearate (see DE 2130480).

An anti-arrhythmic drug containing 0.200 g amiodarone hydrochloride, 0.071 g lactose, corn starch, povidone, colloidal silicon and magnesium stearate is also known (VIDAL, 1992).

The disadvantages of the known drugs are the low in vitro dissolution of the active substances and the relatively low therapeutic plasma concentration.

An arrhythmia drug was prepared containing 100 to 300 mg of amiodarone hydrochloride and excipients in the following proportions: 40 to 90 mg of corn starch, 10 to 30 mg of sodium glucoate starch, 6 to 18 mg of copolividone VA64, 15 to 35 mg mannitol SD200, 0.5 to 35 mg colloidal silica, 6 to 15 mg talc, and 1 to 5 mg magnesium stearate.

Arrhythmia drug is obtained in this technological mode.

The determined amount of amiodarone hydrochloride and corn starch with sodium starch glycolate 2.3: 1 was placed in a mixer-granulator chamber for 3 min. and the resulting mass is wetted with copolividone VA64 and 96% ethanol.

The wetted mass is granulated and dried at a temperature of 40-50 ° C until the moisture content is 3% and passed through a calibration sieve with a diameter of 1mm. Mannitol SD200, colloidal silica, talc and magnesium stearate are added to the dry granulate. After the mixture has been homogenized, tablets are made from it by means of a rotary tablet-forming machine with a flat facet piston of 10 mm diameter and a separation line on one side.

The advantages of the drug developed with amiodarone hydrochloride are: simpler composition, easy reproduction, successful selection of excipients gives very good physico-mechanical parameters, improved degree of dissolution of the active substance in vitro. Therapeutic plasma levels have been demonstrated by bioequivalence studies.

The use of Copolividone VA64 as a binder, due to its hygroscopic properties, protects amiodarone hydrochloride from moisture during storage, and the mannitol SD200 used as an excipient specifically for the production of moisture-sensitive drugs has excellent theological properties allowing the active ingredient to be uniformly distributed, strongly suppressing it and especially improving its dissolution.

Another advantage is the use of starch sodium glucolate because it has very good disintegration properties, which are associated with rapid and active absorption, which ensures good dissolution of the active ingredient.

example.

Tablet containing 200 mg amiodarone:

amiodarone hydrochloride, 200 mg;

corn starch, 68 mg;

starch sodium glucolate, 20 mg;

mannitol SD200, 25 mg;

copolividone VA64.12 mg;

colloidal silica, 2 mg;

talc, 10 mg;

magnesium stearate, 3 mg.

Typically, 30,000 tablets of the above composition are produced using: 6,000 kg of amiodarone hydrochloride; 2,040 kg maize starch and 0,600 kg sodium starch glycolate. The mixture is homogenized and moistened with a solution of 0.360 kg copolividone VA64 in 1.500 kg 96% ethanol.

The wetted mass is granulated through a 2.5 mm sieve, dried at a temperature of 40 to 50 ° C (± 3 ° C) until 3% moisture is retained and passed through a 1 mm calibration sieve. The resulting mixture is homogenized in a turbula blender for 30 min and then tablets with an average weight of 340 mg ± 5 are produced on a rotary tableting machine with 10 mm flat piston, facet and separation line on one side. %.

example.

The results of in vitro assays for the dissolution of amiodarone hydrochloride from the substance according to the present invention in tablets containing 200 mg amiodarone and comparative samples also containing 200 mg amiodarone hydrochloride are shown in Table 1.

table

Sample Proposed material containing 200 mg of amiodarone Compare mass happy dys Proposed material containing 200 mg of amiodarone Level- homemade sis happy dys We suggest material ga, containing 200 mg of amiodarone Level- homemade sis happy dys We offer a substance containing 20C mg amioda- rono 3 Comparative example Duration, degree of dissolution of amiodarone hydrochloride (xi),% of labeled amount After 15 minutes After 30 minutes After 45 minutes After 60 min. 1 tablet 85.15 79.35 94.83 93.66 94.98 95.96 99.27 96.82 2 tablets 82.20 75.77 93.22 89.66 94.78 89.45 98.58 95.50 3 tablets 89.62 95.97 93.00 91.55 98.50 93.66 100.08 98.87 4 tablets 83.03 72.40 93.13 90.50 96.29 96.82 98.71 97.24 5 tablets 86.09 82.50 94.57 93.03 98.69 92.66 99.72 96.40 6 tablets 85.63 81.24 94.31 91.13 98.20 95.55 99.80 94.34 Average, % 85.28 81.21 93.84 91.59 96.91 94.02 99.36 96.53 Standard deviation, % 2.61 8.13 0.82 1.52 1.79 2.71 0.62 1.54 Relative standard deviation,% 3.06 10.00 0.87 1.65 1.85 2.88 0.62 1.60

Comparison of the results shows that the arrhythmia drug produced by the proposed formulation has higher quantitative levels of amiodarone hydrochloride dissolution, defined in minute intervals (up to 60 min) and lower relative standard deviation compared to the comparator samples. These results are confirmed by the good properties of the optimally selected formulation, i.e. higher dissolution of the active ingredient, which makes the drug more bioavailable (see Example 3).

example.

The results of the comparative bioavailability studies of the proposed formulation containing 200 mg of amiodarone hydrochloride labeled "Investigative" (T) and a control sample labeled "Reference" (R) are presented in Table 2 and Figure 1.

A comparative analysis of the results of the pharmaco-kinetic parameters study shows that according to the basic pharmaco-kinetic index, i.e. area under the curve (AUC) (plasma concentration versus time (AUC 0 to 12 h)), the drug according to the invention exhibits higher magnitude values and better statistical indices than the control sample selected. This reflects the steady-state therapeutic plasma levels obtained, guaranteeing high efficacy.

These results are also confirmed by the mean values of the investigated pharmaco-kinetic parameters calculated using a regression analysis software (Table 3).

table

Area under the curve (AUC) (plasma concentration versus time (0 to 24 h)) in study volunteers taking 1 tablet per boom of “Study” (T) and References (R).

Volunteer # Follow R-Reference T-Investigator AUC 0- °∞ (pg / ml.h) First Second Period Period Ratio (T / R) 01 TR 2.65 6.68 0.39671 02 TR 4.43 7.31 0.60602 03 RT 4.82 5.42 1,12448 04 TR 2.56 4.24 0.60377 05 TR 3.07 4.56 0.67325 06 RT 6.12 7.25 1.18464 07 RT 6.26 7.51 1,19968 08 RT 3.69 9.86 2.67209 09 TR 5.28 6.72 0.78571 10th RT 4.38 5.21 1.18950 11th RT 4.31 4.46 1,03480 12th TR 6.48 7.73 0.83829 13th RT 14.83 15.66 1,05597 14th TR 3.31 5.83 0.56775 15th RT 2.60 3.89 1,49615 16th RT 3.72 4.65 1.25000 17th TR 5.52 6.59 0.83763 18th TR 3.44 4.96 0.69355 19th TR 5.54 6.59 0.83764 20th TR 7.29 4.83 1,50932 21st RT 5.00 5.93 1.1860 22nd TR 3.69 5.68 0.64965 23rd TR 5.87 6.99 1,19080 24th RT 3.76 5.11 1,35904

table

Plasma pharmacokinetic parameters averages with standard deviations (SD) and minimum-maximum values.

Suggested composition Investigative (T) Specified example Reference (R) Cmax (pg / ml) 0.317 ± 0.17 0.294 ± 0.12 min-max 0.123-0.694 0.110-0.666 AUC 0- ~ (pg / ml.h) 5.695 ± 2.33 5.663 ± 2.77 min-max 2.56-15.66 2.60-14.83 Tmax (h) 4.88 ± 2.34 5.25 ± 2.63 min-max 1.5-8 2-12

AUC 0- · ° (pg / ml.h) - area under the curve,

Cmax (pg / ml) - peak plasma concentration reached, Tmax (h) - time to peak concentration.

Claims (1)

DEFINITION OF INVENTION Arrhythmia containing (2-butyl-3-benzofuranyl) [4- [2- (diethylamino) ethoxy] -3,5-diiodophenyl] methanone hydrochloride and excipients, characterized in that amiodarone hydrochloride and maize starch the starch sodium glucolate ratio is 2.3: 1 and the ingredients are as follows: 100 to 300 mg of amiodarone hydrochloride, 40 to 90 mg of corn starch, 10 to 30 mg of sodium glucolate starch, 6 to 18 mg of copolividone VA64, 15 to 35 mg of mannitol SD200, 0.5 to 35 mg of colloidal silicon 6 to 15 mg and 1 to 5 mg of magnesium stearate.