JPH0141606B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides that the active ingredient is α-[2-[bis(1-
The present invention relates to an antiarrhythmic drug with long-term function or action, which is methylethyl)amino]ethyl]-α-phenyl-2-pyridineacetamide or one of its salts, its production, and compositions containing the drug.

It is known that the absorption of drugs by the body's systems is of highly variable durability and amount depending on the route of administration. This absorption makes it possible to obtain rapid activity that can last for 2-3 hours in the most advantageous cases.

Various means are resorted to in order to maintain this activity for a certain period of time. It is thus possible from a physical point of view to change the particle shape of the active ingredient, to coat it or to incorporate it into suitable substances. In addition, chemical measures have been taken, such as the use of ion exchange resins or complexation.

In the field of antiarrhythmology, it is particularly useful to obtain drugs whose action is as constant and continuous as possible, since the diseases to be treated very often require uninterrupted treatment over long periods of time.

The inventor has obtained the French special pharmaceutical patent No.
2485M, known antiarrhythmic agents, namely α-[2-[bis(1-methylethyl)amino]ethyl]-α-phenyl-2-pyridineacetamide and its salts such as phosphates, chlorides, We have discovered new delayed forms of bromide, ethylene disulfonate, acetate or sodium bisulfate salts.

The subject of the present invention thus provides a combination of a α-[2-[bis(1-methylethyl)amino]ethyl]-α-phenyl-2-pyridineacetamide or the same with a pharmaceutically acceptable inorganic or organic acid. an ester of glycerin with a fatty acid containing from 10 to 22 carbon atoms, c having a solubility in water at ambient temperature of from 0.2 g to 3
It is a novel antiarrhythmic drug with long-term function, characterized by containing sugars in the g/ml range.

Esters of glycerin and fatty acids can be mono-, di- or triesters of glycerin formed with fatty acids containing 10 to 22 carbon atoms, such as mono-, di- or triesters of glycerin. , di- and tristearates,
Mention may be made of mono-, di- and tripalmitic acid esters of glycerin, di- and trilauric acid esters of glycerin, mono-, di- and tricapric acid esters of glycerin, and mono-, di- and trimyristate esters of glycerin. Can be done. These esters can be used alone or in combination.

Solubility in water at ambient temperature is 0.2g~3
The inert vehicle in the g/ml range can be, for example, a sugar such as sucrose, lactose or glucose.

Among the drugs constituting the subject matter of the present invention, α-
[2-bis(1-methylethyl)amino]ethyl]
-A drug characterized by containing α-phenyl-2-pyridine acetamide phosphate.

Also, α-[2-[bis(1-methylethyl)
Amino]ethyl]-α-phenyl-2-pyridine acetamide about 60% to 80%, 10% ester of glycerin with fatty acids containing 10 to 22 carbon atoms
~30% and solubility in water at ambient temperature
Mention may be made of drugs containing 2% to 12% sugars in the range of 0.2 to 3 g/ml.

Furthermore, among this drug, which constitutes the subject of the invention, mention may be made in particular of a drug characterized in that the ester of glycerin and a fatty acid containing 10 to 22 carbon atoms is glyceryl monostearate. .

Also, a drug characterized in that the inert substance has a solubility in water at ambient temperature within the range of 1.5 g to 2.5 g/ml, in particular in that the saccharide of the inert vehicle is constituted by sucrose. There are things that do.

Within the scope of the invention, it has proven advantageous to add, in addition to the three components defined above, binders and lubricants, such as polyvinylpyrrolidone.

A subject of the invention is thus also a medicament, characterized in that it comprises a medicament as defined above and additionally polyvinylpyrrolidone and a lubricant.

The lubricant can be, for example, talc, stearic acid, zinc, calcium or aluminum salts of stearic acid, preferably magnesium stearate.

The binder and lubricant can be added in conventional proportions, for example from 0.5% to 3% each, preferably in the range 0.5% to 1.5% binder and 2% lubricant.
-3% range.

The drugs defined above have significant long-term antiarrhythmic properties. Such properties will be further exemplified in "Clinical Studies" below.

Due to this property, the drug forming the subject of the invention can be used for the prophylactic treatment of dysrhythmia, arrhythmia recurrence, paroxysmal tachycardia, or for the prevention of atrial or atrioventricular premature contractions as well as digital It can be used in the curative treatment of extrasystoles and biphasic phenomena by medication.

Typical dosages may vary depending on the compound used, the subject and the associated condition, but for example, it may be 100% per dose when administered orally to humans once in the morning and evening.
mg to 500 mg of α-[2-[bis(1-methylethyl)amino]ethyl]-α-phenyl-2-pyridine acetamide phosphate.

Thus, another subject of the invention is a process for the preparation of a medicament, characterized in that the various components defined above are mixed according to techniques known per se.

Yet another subject of the invention is a pharmaceutical composition comprising at least one drug as described above. This composition is intended for oral use.

The pharmaceutical compositions can be presented in the pharmaceutical forms currently used in human medicine, such as plain or sugar-coated compressed tablets, gelatin capsules and granules. Therefore, this product is manufactured according to a conventional method.

When formulating the pharmaceutical compositions defined above, other excipients such as gum arabic, aluminum hydroxide, colloidal silica, starch and preservatives commonly used in such compositions may be added.

Examples of the present invention are shown below, but the present invention is not intended to be limited thereby.

Example: Coated compressed tablets Coated compressed tablets were prepared with the following composition: -α-[2-[bis(1-methylethyl)amino]ethyl]-α-phenyl-2-pyridine acetamide phosphate (Disopyramide phosphate)...322.5mg - Glyceryl monostearate...90.0mg - Powdered sucrose...30.0mg - Polyvinylpyrrolidone...5.0mg - Magnesium stearate...12.5mg - Coating (hydroxypropyl methyl cellulose,
glucose, propylene glycol)
...10.0mg That is, α-[2-bis(1-methylethyl)amino]ethyl]-α-phenyl-2-pyridineacetamide phosphate, glyceryl monostearate, and sugar are mixed homogeneously, and this mixture is Melt at about 65° C., check the resulting granules on a sieve, moisten the granules with an aqueous solution of polyvinylpyrrolidone, dry and check on a sieve again, add magnesium stearate and then sieve the granules. Pass through a tablet forming machine.

Coating is accomplished by spraying and simultaneous drying of an aqueous solution of a mixture of hydroxypropyl methylcellulose, glucose and propylene glycol.

Clinical study of delayed activity After oral administration to humans of one compressed tablet of disopyramide phosphate (equivalent to 250 mg of disopyramide base) and two gelatin capsules containing 100 mg of disopyramide, in each case: Compare disopyramide concentration in plasma as a function of time.

This study involved six male patients between the ages of 21 and 24 who were taking multiple medications.

0 hours after medication (just before medication) and 0.5-1-1.5
-2-3-4-5-6-8-12-15-24-30-36
- Plasma samples (10 ml each time) were collected at each 48 hour period. After extracting the collected sample using ethyl acetate, it was analyzed by high-pressure liquid phase chromatography.

Since the content of disopyramide in gelatin capsules and compressed tablets is different, the concentration was expressed as the dose (%) per plasma so that the concentration in plasma obtained after administration could be directly compared.

a Time to reach maximum concentration: The maximum concentration in plasma is 2.58 hours for the gelatin capsule form (Figure 1) and for the compressed tablet form (Figure 2).
Figure) is achieved in 4.50 hours.

b Amount of active ingredient reaching the systemic circulation: The area between the curve showing the plasma concentration of the test compound as a function of time and the abscissa axis is calculated. Virtually the same result is obtained.

Gelatin capsules: 13.6% dose ^{- 1} h Compressed tablets: 13.2% dose ^{- 1} h represents the plasma volume in liters and h represents the time (hr).

c Latency period until onset of action Gelatin capsules: 0.34 h Compressed tablets: 0.29 h Conclusions Thus, the maximum concentration peak is delayed more in the compressed tablet form, so the reabsorption of the compound in the compressed tablet form versus the gelatin capsule form Significant delays can be confirmed.

Also, the total amount of active ingredient reaching the systemic circulation is approximately the same in both compressed tablet and gelatin capsule forms. So, in the end,
At the same time the active ingredient appears in the plasma.

Therefore, in the case of compressed tablets, we are dealing with drugs with long-term action.

[Brief explanation of drawings]

Figure 1 shows the time course of the plasma active ingredient concentration in the case of gelatin-capsule shape, and Figure 2 shows the
Figure 2 shows the change in plasma active ingredient concentration over time in the case of compressed tablet form.

Claims (1)

[Claims] 1 a α-[2-[bis(1-methylethyl)]
[amino]ethyl]-α-phenyl-2-pyridineacetamide or one of its addition salts with a pharmaceutically acceptable inorganic or organic acid; b. glycerin and a fatty acid containing 10 to 22 carbon atoms; ester with c solubility in water at ambient temperature of 0.2 g to 3
A novel antiarrhythmic drug with long-term function, characterized by containing sugars in the g/ml range. 2. The drug according to claim 1, which contains α-[2-[bis(1-methylethyl)amino]ethyl]-α-phenyl-2-pyridine acetamide phosphate. 3 α-[2-[bis(1-methylethyl)amino]ethyl]-α-phenyl-2-pyridineacetamide Esters of glycerin with fatty acids containing about 60% to 80% and 10 to 22 carbon atoms 10%~30
% and solubility in water at ambient temperature is 0.2
The drug according to claim 1 or 2, characterized in that it contains 2% to 12% saccharides in the range of g to 3 g/ml. 4. Claim 1, characterized in that the ester of glycerin and a fatty acid containing 10 to 22 carbon atoms is glyceryl monostearate.
The drug according to any one of items 3 to 3. 5 The solubility of sugars in water at ambient temperature is
The drug according to any one of claims 1 to 4, characterized in that the amount is in the range of 1.5 g to 2.5 g/ml. 6. The drug according to claim 5, wherein the saccharide is composed of sucrose. 7 Claims 1 to 7 further contain polyvinylpyrrolidone and a lubricant.
The drug described in any of Item 6.