RU2363464C2 - Tableted dosage form of felodipine with modified release, method and composition for making said tableted dosage form and medical application - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: pharmaceutical composition for making tableted dosage form with modified release for oral administration of calcium channel blocker-felodipine contains felodipine or its pharmaceutically acceptable salt, a carrier for modified release and a hydration gel accelerator. The carrier for modified release is a salt of alginic acid with an alkali metal. The hydration gel accelerator is hydroxypropyl methylcellulose.

EFFECT: provision for relatively fast (during several hours) release of felodipine, with simultaneous prolonged retention of its concentration in blood plasma at a stable high level, and is characterised by low cost of production.

20 cl, 1 dwg, 2 tbl, 3 ex

Description

The invention relates to the field of medicine and the pharmaceutical industry, in particular to a tablet dosage form of a calcium channel blocker (preferably felodipine) or its pharmaceutically acceptable salt, with a modified release, to a composition for its manufacture, as well as to a method for its preparation and its use for treatment diseases in which calcium channel blockers are indicated.

Calcium ions play an important role in the regulation of various processes of the body. Penetrating into cells, they activate bioenergetic processes (the conversion of ATP into cAMP, protein phosphorylation, etc.), ensuring the implementation of the physiological functions of cells. In increased concentration (with ischemia, hypoxia, and other pathological conditions), they can excessively enhance the processes of cellular metabolism, increase the oxygen demand of tissues and cause various destructive changes. The transmembrane transfer of calcium ions is carried out through special channels, which are macromolecular proteins that dissect the peptide biolayers of the cell membrane. They are called calcium or “slow” channels (unlike the “fast” channels through which other ions are transported). In the body, the flow of calcium ions through the membrane is regulated by a number of endogenous factors (acetylcholine, catecholamines, serotonin, histamine, etc.) or by the membrane potential. For a number of compounds representing the chemical structure of phenylalkylamines (verapamil, gallopamil, etc.), 1,4-dihydropyridines (felodipine, nifedipine, nitrendipine, amlodipine, nicardipine, etc.), benzothiazepines (diltiazem, etc.) and others (cinnarizine , flunarizine), has been shown to inhibit the passage of calcium ions through "slow" channels. They are united under the group name - calcium channel blockers (calcium antagonists).

The range of pharmacological activity of calcium antagonists includes effects on myocardial contractility, activity of the sinus node and AV conduction, vascular tone and vascular resistance, function of the bronchi, organs of the gastrointestinal tract and urinary tract. These drugs have the ability to inhibit platelet aggregation and modulate the release of neurotransmitters from presynaptic endings. The main use of calcium ion antagonists is due to their effect on the cardiovascular system. Causing vasodilation and decreasing OPSS, they lower blood pressure, improve coronary blood flow and reduce myocardial oxygen demand. These drugs lower blood pressure in proportion to the dose, in therapeutic doses they slightly affect normal blood pressure, do not cause orthostatic effects. Preparations of this group, affecting the excitability and conduction of the heart muscle, are used as antiarrhythmic drugs. The advantage of calcium antagonists is the absence of an adverse effect on lipid metabolism, electrolyte balance and carbohydrate tolerance. Verapamil, nifedipine, diltiazem are characterized by a short duration of action, which necessitates a 3-4-fold intake during the day and is accompanied by fluctuations in the vasodilating and hypotensive effect. Dosage forms with a modified release of the drug substance provide a constant therapeutic concentration and increase the duration of the drug.

Calcium antagonists have been created (mainly dihydropyridines), which are distinguished by a highly specific effect on individual organs and vascular regions (for example, nimodipine - on the cerebral vessels).

One of the most important representatives of this class is felodipine (INN; chemical name is 4- (2,3-dichlorophenyl) -1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylic acid ethyl methyl ether), which is a selective class II calcium channel blocker from the group of 1,4-dihydropyridine derivatives. Like other dihydropyridine derivatives, felodipine has a significantly higher affinity for the calcium channels of smooth muscle cells of arterial vessels than for the calcium channels of cardiomyocytes. By blocking calcium channels and disrupting the flow of calcium ions into the smooth muscle cells of arterial vessels, it causes their expansion, reduces the total peripheral vascular resistance (OPSS) and lowers blood pressure, reduces the afterload on the heart, practically has no inhibitory effect on myocardial contractility and conductivity, and causes a moderate reflex tachycardia, increases coronary blood flow, and also has a moderate diuretic (natriuretic) effect.

The prior art discloses a method for producing calcium antagonist tablets containing substituted dihydropyridines (nifedipine or felodipine) as the active principle, which consists in dissolving the active principle in a semi-solid or liquid non-ionic solubilizer, using Cremophor (polyoxyethylene castor oil) ( USSR patent for the invention SU 1743332, publ. 06.23.1992).

The disadvantage of this method is that it is necessary to use significant amounts of non-ionic surfactant (due to the fact that felodipine is a sparingly soluble substance), which has a softening effect on the prepared dosage form. This, in turn, requires an increase in the content of other inactive components in the tablet. In addition, it is known that polyoxyethylated castor oil in some cases can lead to the development of anaphylactic reactions.

Also from the prior art (RF patent for the invention RU 2295358, published March 20, 2007), a composition intended for the modified release of the active principle, proposed as the closest analogue of the claimed invention, is known, including an antihypertensive agent such as calcium channel blockers (including dihydropyridine calcium channel blockers such as nifedipine, felodipine, isradipine, etc.) containing a drug substance, a modified drug release carrier and a gel hydration accelerator in which the weight ratio of the drug substance to the modified carrier the release of the drug and the gel hydration accelerator is in the range 1: 3-45: 0.1-15, the carrier is a mixture of sodium alginate and xan ANOVA gum having a weight ratio of 1: 0.1-10, and the gel hydration accelerator is a mixture of hydroxypropyl methylcellulose and propylene glycol alginate having a weight ratio of 1: 0.05-20.

This drug, proposed as the closest analogue (prototype) of the claimed invention, is characterized by a complex production technology, which complicates the cost of its production. In this regard, there is a need to create more affordable domestic preparations of calcium channel blockers (preferably dihydropyridine calcium channel blockers, in particular felodipine) with modified release.

In addition, when using tablet dosage forms with modified release, in some cases there is a need for a relatively quick (within several hours) achievement of effective plasma concentrations of the drug, followed by a prolonged release of the remaining amount of active principle.

To solve these problems, the applicant has developed a composition for the manufacture of a modified release tablet dosage form for oral administration of a drug, comprising a drug selected from a calcium channel blocker and its pharmaceutically acceptable salt, a carrier for modified drug release and a gel hydration accelerator, characterized in that the quantitative ratio of the drug substance, the carrier for modified excretion the booster and gel hydration accelerator is 1: 0.4-1: 4.0-12.0, the carrier does not contain xanthan gum, and the gel hydration accelerator is hydroxypropylmethyl cellulose and does not contain propylene glycol alginate.

Also in accordance with the present invention, there is provided a tablet dosage form for oral administration with a modified release of a drug selected from a calcium channel blocker and its pharmaceutically acceptable salt, consisting of a core and a film coating covering it, characterized in that the core is made from the composition of the invention.

Also provided is a method of obtaining the inventive tablet dosage form, including:

a) mixing sieved powders of lactose and felodipine,

b) the addition of calcium hydrogen phosphate dihydrate,

c) mixing

g) wetting the mixture with an aqueous solution of collidone,

d) thorough mixing until even distribution of moisture,

e) mixing the mass for 5-7 minutes,

g) drying the wet granulate,

h) granulation and

i) dusting of magnesium with stearate and aerosil,

k) tableting the resulting mass,

characterized in that to the mixture of lactose, felodipine, calcium phosphate and collidone obtained in stage (g), hydroxypropyl methylcellulose in an amount of 15-20 wt.% and a salt of alginic acid and an alkali metal in an amount of 2.0-2.5 wt. %

The finished tablets are preferably coated with a film shell made from Selecout (a commercially available mixture for the manufacture of coatings for solid oral dosage forms, consisting of hydroxypropyl methylcellulose, copolymers of vinylpyrrolidone and vinyl acetate, polyethylene glycol, titanium dioxide and iron oxide, in a mass ratio of components: 0.4: 0, 07: 0.09: 0.07: 0.06).

The invention also discloses the use of a tablet dosage form of a calcium channel blocker or a pharmaceutically acceptable salt of the invention for treating a condition in which calcium channel blockers are required, and a method for treating a condition in which calcium channel blockers are required, including the oral administration of a tablet dosage form of calcium blocker channels or its pharmaceutically acceptable salt with a modified release of the active component according to the invention.

Below are examples of compositions according to the invention and methods for their preparation, illustrating the claimed invention (without limiting the scope of claims).

Examples 1-3.

Obtaining the composition of the calcium channel blocker in accordance with the invention.

Powders of felodipine or its pharmaceutically acceptable salt, lactose, magnesium stearate, calcium hydrogen phosphate dihydrate and aerosil (in amounts taken in accordance with table 1) are separately sieved through a sieve; sifted powders of lactose and felodipine are mixed, calcium hydrogen phosphate dihydrate is added, mixed. Humidify the resulting mixture with an aqueous solution of Collidone 30, mix until a uniform distribution of moisture. Benecel MP 824 and sodium alginate (in amounts taken in accordance with Table 1) are added to the moistened mass, the mass is mixed for 5-7 minutes. The wet granulate is dried, granulated, dusted with magnesium stearate and aerosil (colloidal silicon dioxide).

Table 1. Compositions of felodipine or a pharmaceutically acceptable salt thereof with a modified release in accordance with the invention F1 F2 F3 Felodipine or its salt, kg * 5,0 10.0 7.5 GPMC, kg 32.6 67.65 46.7 Sodium alginate, kg 5,0 8.0 7.0 Lactose, kg 61.3 127.2 88.2 Magnesium stearate, kg 1,5 3.0 2.25 Calcium hydrogen phosphate dihydrate, kg 65.0 130.1 90.3 Kollidon 30, kg 6.0 12.0 9.0 Aerosil (SiO ₂ colloidal), kg 1,5 2,8 1.9 * - in terms of felodipine base

The resulting mass is tabletted, respectively 177.9 (F1), 360.75 (F2) and 252.85 (F3) kg of modified release felodipine tablet cores are coated, which are coated with an aqueous suspension of the film coat (Selecout).

The applicant conducted studies of the in vitro dissolution kinetics of modified release felodipine tablets made from the composition according to the invention (formulations F1-F3) and tablets made from the composition according to patent RU 2295358. The amount of felodipine transferred to the solution was measured after 2, 4, 6, 8, 10, 12, 16, 20, 24 hours. The results are presented in table 2 and in the drawing.

Table 2. Time h Sample F1 Sample F2 Sample F3 Tablets according to RU 2295358 % released substance 2 24.0 19.0 22.0 5,0 four 47.0 40,0 43,2 10.0 6 63.0 68.0 69.0 20,0 8 75.0 72.0 77.0 26.0 10 79.0 78.0 80.0 37.0 12 82.0 80.0 84.0 44.0 16 86.0 82.0 87.0 64.0 twenty 90.0 91.0 91.0 78.0 24 99.0 98.0 97.4 97.0

The results show that, in comparison with the prototype, the composition for the manufacture of a modified release tablet dosage form in accordance with the present invention, as well as the tablet dosage form made therefrom, can reach a maximum plasma concentration of felodipine at the same time. ensuring its long retention, and are characterized by lower cost, which is the inventive step of the present invention.

Claims (20)

1. A pharmaceutical composition for the manufacture of a modified release tablet dosage form for oral administration of a calcium channel blocker-felodipine comprising felodipine or a pharmaceutically acceptable salt thereof, a modified release carrier comprising an alkaline metal salt of an alginic acid and a gel hydration accelerator comprising hydroxypropyl methylcellulose while the mass ratio of felodipine, the specified carrier for the modified release Denia and said gel hydration accelerator is 1: 0.4-1.0: 4,0-12,0. 2. The pharmaceutical composition according to claim 1, characterized in that the salt of alginic acid with an alkali metal is sodium alginate. 3. The pharmaceutical composition according to claim 1, characterized in that the hydroxypropylmethyl cellulose is a Benecel MP 824. 4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that it further comprises colloidal silicon dioxide in an amount of 0.6-1 wt.%. 5. The pharmaceutical composition according to claim 4, characterized in that it further comprises a stearic acid salt with an alkaline earth metal in an amount of 0.3-1.77 wt.%. 6. The pharmaceutical composition according to claim 5, characterized in that the stearic acid salt with an alkaline earth metal is magnesium stearate. 7. The pharmaceutical composition according to claim 6, characterized in that it further comprises povidone in an amount of 3.0-5.0 wt.%. 8. The pharmaceutical composition according to claim 7, characterized in that the povidone is Collidone 30. 9. The pharmaceutical composition according to any one of claims 1 to 8, characterized in that it further comprises calcium hydrogen phosphate dihydrate in an amount of 35-40 wt.%. 10. The pharmaceutical composition according to claim 9, characterized in that it further comprises the required amount of lactose as a filler. 11. A tablet dosage form of a modified release felodipine for oral administration comprising felodipine or a pharmaceutically acceptable salt thereof, a modified release carrier comprising an alkaline metal salt of alginic acid and a gel hydration accelerator comprising hydroxypropyl methylcellulose consisting of a core and a film coating thereof shell, characterized in that the core is made of a composition according to any one of claims 1 to 10. 12. The tablet dosage form according to claim 11, characterized in that the film shell is made of a mixture of hydroxypropyl methylcellulose, polyethylene glycol 400, polyethylene glycol 6000 and pigments. 13. The tablet dosage form according to claim 12, wherein the pigments are selected from titanium dioxide, yellow iron oxide and quinoline yellow. 14. A method of obtaining a tablet dosage form with a modified release of the drug from the composition according to any one of claims 1 to 10, including:
a) mixing a sifted powder of a drug substance selected from felodipine or a pharmaceutically acceptable salt thereof with a sifted excipient powder,
b) the addition of calcium hydrogen phosphate dihydrate,
c) mixing
g) moistening the mixture with an aqueous solution of povidone,
d) thorough mixing until even distribution of moisture,
e) mixing the mass for 5-7 minutes,
g) drying the wet granulate,
h) granulation and
i) dusting with a salt of stearic acid and an alkaline earth metal, and silicon dioxide colloidal,
k) tableting the resulting mass,
characterized in that to the mixture of filler, felodipine, calcium phosphate and povidone obtained in stage (g), add hydroxypropylmethyl cellulose in an amount of 10-30 wt.% and a salt of alginic acid with an alkali metal in an amount of 2.0-2.5 wt. %, and the resulting core is covered with a film coating. 15. The method of producing a tablet dosage form according to 14, characterized in that the film shell is made of a mixture of hydroxypropyl methylcellulose, polyethylene glycol 400, polyethylene glycol 6000 and pigments. 16. The method of producing a tablet dosage form according to claim 15, characterized in that the pigments are selected from titanium dioxide, yellow iron oxide and quinoline yellow. 17. The use of the tablet dosage form according to claim 11 for treating a condition in which it is necessary to take calcium channel blockers-felodipine. 18. The use of claim 17, wherein the condition in which felodipine is needed is arterial hypertension, Raynaud's syndrome, and an unstable form of angina pectoris in case of intolerance or ineffectiveness of beta-blockers or nitrates. 19. A method of treating a condition in which it is necessary to take a calcium channel blocker-felodipine, comprising orally administering a tablet dosage form of felodipine or a pharmaceutically acceptable salt thereof with a modified release of the active component according to claim 11. 20. The treatment method according to claim 19, where the condition in which felodipine is needed is arterial hypertension, Raynaud's syndrome and an unstable form of angina pectoris in case of intolerance or ineffectiveness of beta-blockers or nitrates.

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