RU2554815C1 - Hypotensive means - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention represents a hypotensive means, which contains felodipinum as an active component, as well as target additional components: mesoporous silicon dioxide, lactose, hypromeloza. Realisation of the invention ensures the high technological efficiency of the claimed medical means production with the provision of a prolonged release of an active substance with the application of available components. Felodipinum is included into spherical particles with a highly developed mesoporous structure of silicon oxide.

EFFECT: increase of stability in storage and protection from unfavorable environmental factors.

4 cl, 4 ex

Description

The invention relates to medicine, in particular to pharmaceutical preparations used to treat arterial hypertension.

Arterial hypertension (AH) remains a serious medical problem in many countries of the world. For example, in Russia 23-30% of the population suffers from this disease. AH is also a risk factor for other diseases of the cardiovascular system. The results of epidemiological studies showed a significant relationship between hypertension and coronary heart disease (CHD), cerebral stroke, chronic heart failure, and chronic renal failure.

Currently, various classes of antihypertensive drugs are used to treat hypertension. These include thiazide and thiazide-like diuretics, beta-blockers, angiotensin converting enzyme inhibitors (ACE inhibitors), calcium antagonists (AK), blockers of AT1-angiotensin receptors, blockers of α1-adrenergic receptors, agonists of I1-imidazolinergic receptors, α1-imidazolinergic receptors, α1-receptors.

Calcium antagonists, which include derivatives of dihydropyridine (nifedipine, amlodipine, isradipine, nisoldipine, nitrendipine, felodipine, etc.) have long been used in cardiology due to their high efficacy and good tolerability.

One of the derivatives of dihydropyridine is felodipine (4- (2,3-dichlorophenyl) -1,4-dihydro-2,6-dimethyl-3,5-pyridine-dicarboxylic acid ethyl methyl ester). It is considered the safest in the treatment of hypertension in patients, especially with overt or latent systolic dysfunction of the left ventricle. The drug has an insignificant effect on the contractile function of the myocardium. However, when using it, physicians are faced with the problem of very low bioavailability. According to some reports, it is 12-16%. The half-life of felodipine for the retard form is 10-36 hours and the time to reach the maximum plasma concentration is 2-8 hours (PHARMACOTHERAPY OF HYPERTENSIVE DISEASE. PART 4. CALCIUM ANTAGONISTS AS ANTIHYPERTENSIVE DRUGS, Sidorenko B.A., Preobrazhensky D. : //www.rmj.ru/articles_2313.htm).

The well-known preparations Plendil (AstraZeneca AB, Sweden) and Felodip ("IVAX Pharmaceuticals" sro, Czech Republic) contain hypromellose and lactose [Normative documentation “Plendil. Long-acting tablets, coated 2.5 mg, 5 mg, 10 mg "AstraZeneca Sweden; Radar, electronic reference book, [Access mode: http://www.rlsnet.ru]; MASHKOVSKY M.D. Medicines - M., 2007, p.432]]. The use of lactose as an auxiliary substance improves the dissolution of felodipine, the introduction of hypromellose slows the release of the active substance. The use of microcrystalline cellulose and other insoluble components makes the release of felodipine more uniform. However, these formulations have disadvantages associated with insufficient release of felodipine in the first hours.

Patents are known in which attempts have been made to develop improved forms of felodipine with delayed action.

Patent RU 2363464 (C2), publ. 2009-08-10 describes a composition for the manufacture of a modified release tablet formulation for oral administration of a drug comprising felodipine or a salt thereof, HPMC, sodium alginate, lactose, magnesium stearate, calcium hydrogen phosphate dihydrate, collidone 30, aerosil.

CN 101953837, publ. 01.01.26 describes Felodipine slow release tablets containing a cyclodextrin clathrate compound, a filler, microcrystalline cellulose, a lubricant and a glidant.

CN 102552200, publ. 2012.07.11 describes slow release tablets of felodipine containing high viscosity hydroxypropyl methyl cellulose and low viscosity hydroxypropyl methyl cellulose and a water soluble excipient.

CN 101744786, publ. 06/06/2013 discloses sustained release felodipine tablets that include a core containing felodipine, polyoxyethylene (20) sorbitan monooleate, hydroxypropyl methylcellulose, microcrystalline cellulose, magnesium stearate, finest silica powder and ethanol solution.

As can be seen from the prior art, hydroxypropyl methylcellulose (HPMC) is preferably used to slow the release profile in systems.

It is known that the ideal release profile is a zero-order dependence when the transition of the active substance from the dosage form to the solution is described as a linear function.

However, a constant rate of isolation of zero order from solid dosage forms, such as tablets or capsules of powders, is not what should be immediately expected from moderately and poorly soluble ingredients, and it is difficult to achieve, since many parameters must be taken into account.

As experimental studies show, one cannot expect a priori the kinetics of the isolation of zero order with moderately soluble calcium antagonists such as dihydropyridine, such as felodipine, in HPMC systems. Zero-order isolation kinetics should be considered as a special case, which can only occur with certain dosage forms.

In recent years, ordered porous materials with the possibility of their use as drug delivery systems have been increasingly studied. Depending on the pore size, inorganic materials can be classified as microporous, mesoporous or macroporous.

There are attempts to create forms with controlled selection based on similar media. For example, published applications CN 103007290 (A) - Nano-carrier particle controllable in drug release and preparation method thereof, GB 2507983 (A) - Mesoporous silica particles and their use in drug delivery, etc. However, these technical solutions do not pay attention to zero the order of release and bioavailability of antihypertensive agents.

As the closest analogue may be indicated international application WO 2006026840 (A2). The application discloses a controlled release from a delivery system containing a biologically active compound and a carrier matrix, which is an amorphous microporous non-fibrous silicon or titanium oxide loaded with said biologically active compound and where micropores from said carrier matrix have an average size in the range of 0, 4 to 2.0 nm. At least 50% of the biologically active compound is molecularly dispersed in the pores of said support matrix. As a possible active compound, felodipine is mentioned in the list. There is no concrete example. Its pharmacokinetics and bioavailability are not discussed.

The problem to which the invention is directed, is to obtain a new finished prolonged dosage form of felodipine that meets all pharmacopoeial requirements, the qualitative and quantitative composition of which will ensure the high manufacturability of this drug while ensuring guaranteed disintegration and complete release of drugs from it using available components .

To solve this problem, it is proposed to include felodipine in the structure of silicon oxide with a mesoporous structure, from which the active substance is released deferred, and additional prolongation is ensured by the introduction of hypromellose. The composition also contains lactose, which performs a number of functions, including a binder, dispersing, sweetening effect.

Thus, the object of the invention is a hypotensive agent in the form of a solid dosage form for oral administration containing particles of silicon oxide with a mesoporous structure, the pores of which with an average diameter of 2 to 50 nm are filled with felodipine, lactose and hypromellose in the ratio of components in wt.%:

Felodipine - 0.48-10.0

Lactose Monohydrate - 0.25-39.0

Hypromellose -0.25-50.0

Silicon dioxide colloidal (Syloid) - 1.0-99.0.

Preferably, silica particles with a mesoporous structure, the pores of which are filled with felodipine, are obtained by dissolving felodipine in ethanol by heating to 40-45 ° C, followed by the introduction of colloidal mesoporous dioxide into the silicon solution, stirring for 3-5 minutes and drying in vacuo.

The final form may or may not contain up to 30 wt.% Ethanol.

The felodipine substance can be obtained by any known method, for example, described in patent EP 0007293 (B1) - 1982-06-23, application WO 9725313 (A1) - 1997-07-17, US 5310917 (A) - 1994-05-10.

Silica particles with a mesoporous structure have pore sizes of 2 to 50 nm. Colloidal silicon dioxide is used, in particular, such as Syloid (https://grace.com/pharma-and-biotech/en-us/Documents/Syloid/M417_Syloid%20Anti-Caking%20App%20NoteFINAL.pdf).

Hypromellose has a large molecular weight (86,000 daltons) and, thus, is slowly absorbed.

Lactose can be either a monohydrate or anhydrous lactose. You can use part of the lactose (up to 30%) in the form of micronized lactose with a particle size of D50 less than 5 microns.

The solid dosage form is preferably a tablet or granulate, which can be packaged in capsules or sachets.

The possibility of carrying out the invention can be illustrated by the following examples.

Example 1. Get tablets weighing 200 mg, which contain 20 mg of felodipine and 1% mesoporous silicon dioxide. Ethyl alcohol is measured in a flask and felodipine is added. If necessary, the solution is heated to 40-45 ° C. Mesoporous silicon dioxide is introduced into the resulting solution and mixed for 3-5 minutes. A mass is formed that preserves the flow properties with light agglomeration. During the drying process, the signs of agglomeration disappear. The resulting sorption complex is dried in vacuum or on pallets in a layer 1-1.5 cm thick. In this case, the amount of alcohol decreases to 30% relative to the total weight of the sorption complex. Next, hypromellose and lactose are added. 200 mg tablets are compressed from the obtained granulate.

Felodipine - 20

Lactose Monohydrate - 78

Hypromellose - 100

Silicon Colloidal Dioxide (Syloid) - 2

The weight of the tablet is 200 mg.

Used pharmaceutical composition with the stated ratio of the components provides optimal physico-chemical and technological properties of the dosage form and high bioavailability of the drug substance. According to the “dissolution test”, felodipine is released into the dissolution medium by 10% in an hour, 30% in 2 hours, 60% in 5 hours, and 80% in 7 hours [US Pharmacopoeia: USP 29. National formulary: in 2 t : [trans. from the English.]. - M.: GEOTAR-Media, 2009. - T. 2. - 1800 p.], A description of the OFS “Dissolution” methodology.

Example 2. Receive capsules weighing 411 mg, which contain 1 mg of felodipine and 49% mesoporous silicon dioxide. The granulate is prepared analogously to claim 1, then the granulate is packaged in capsules.

Felodipine - 1

Silicon Colloidal Dioxide (Syloid) - 200

Lactose Anhydrous - 10

Hypromellose - 200

The weight of the capsule is 411 mg.

Used pharmaceutical composition with the stated ratio of the components provides optimal physico-chemical and technological properties of the dosage form and high bioavailability of the drug substance. According to the “dissolution test”, felodipine is released into the dissolution medium by 10% in an hour, 30% in 2 hours, 60% in 5 hours, and 80% in 7 hours [US Pharmacopoeia: USP 29. National formulary: in 2 t : [trans. from the English.]. - M.: GEOTAR-Media, 2009. - T. 2. - 1800 p.], A description of the OFS “Dissolution” methodology.

Example 3. Receive capsules weighing 200 mg, which contain 1 mg of felodipine and 99% mesoporous silicon dioxide. The granulate is obtained analogously to claim 1, then the granulate is packaged in capsules.

Felodipine - 1

Silicon Colloidal Dioxide (Syloid) - 198

Hypromellose - 0.5

Lactose Anhydrous - 0.5

The weight of the capsule is 200 mg.

Used pharmaceutical composition with the stated ratio of the components provides optimal physico-chemical and technological properties of the dosage form and high bioavailability of the drug substance. According to the “dissolution test”, felodipine is released into the dissolution medium by 10% in an hour, 30% in 2 hours, 60% in 5 hours, and 80% in 7 hours [US Pharmacopoeia: USP 29. National formulary: in 2 t : [trans. from the English.]. - M.: GEOTAR-Media, 2009. - T. 2. - 1800 p.], A description of the OFS “Dissolution” methodology.

Example 4. The granulate is obtained similarly to claim 1, then packaged in a sachet of 4.12 g with the addition of a measuring spoon of 200 mg

Felodipine - 20

Silicon Colloidal Dioxide (Syloid) - 2000

Lactose - 100

Hypromellose 2000

The mass of one sachet is 4.12 g.

Used pharmaceutical composition with the stated ratio of the components provides optimal physico-chemical and technological properties of the dosage form and high bioavailability of the drug substance. According to the “dissolution test”, felodipine is released into the dissolution medium by 10% in an hour, 30% in 2 hours, 60% in 5 hours, and 80% in 7 hours [US Pharmacopoeia: USP 29. National formulary: in 2 t : [trans. from the English.]. - M.: GEOTAR-Media, 2009. - T. 2. - 1800 p.].

The resulting drug is used for hypertension.

The positive effect is that in addition to one prolonged additive (hypromellose), a nanostructured substance is introduced - mesoporous silicon oxide. The drug is prolonged due to slow diffusion from the pores of silicon oxide. When taken orally, the liquid contents of the intestine enter the space of the mesoporous structure of silicon oxide and dissolve felodipine. In this case, the environment is a granulate or tablet. Further, the drug substance diffuses inside the granulate or tablet, after which it enters the intestinal absorption zone, thus, prolongation is achieved due to the mesoporous structure of silicon oxide, and also due to the slowly soluble structure of the tablet or granule. The selected formulation provides higher bioavailability and effective release kinetics. The new form increases the stability of felodipine during storage and protects against adverse environmental factors.

Claims (4)

1. Antihypertensive agent, characterized in that it is in the form of a solid dosage form for oral administration containing colloidal silicon dioxide particles with a mesoporous structure, the pores of which with an average diameter of 2 to 50 nm are filled with felodipine, lactose and hypromellose in the following ratio of components in wt.%:
Felodipine - 0.48-10.0
Lactose - 0.25-39.0
Hypromellose - 0.25-50.0
Silicon dioxide colloidal - 1.0-99.0. 2. Antihypertensive agent according to claim 1, characterized in that it contains up to 30 wt.% Ethanol. 3. The antihypertensive agent according to claim 1 or 2, characterized in that the colloidal silicon dioxide particles with a mesoporous structure, the pores of which are filled with felodipine, are obtained by dissolving felodipine in ethyl alcohol when heated to 40-45 ° C, followed by the introduction of colloidal dioxide into silicon solution mesoporous, stirring for 3-5 minutes and drying in vacuo. 4. The antihypertensive agent according to claim 1 or 2, characterized in that the solid dosage form is a tablet or granules, which can be packaged in capsules or sachets.