RU2393862C1 - Solid dosage form of clopidogrel and method for preparing thereof - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry and concerns a solid dosage form that exhibits the antiaggregatory activity and contains, wt %: clopidogrel hydrosulfate - 15-45; microcrystalline cellulose - 7-20; talc-1-3; sodium croscarmellose - 1-4; low-molecular polyvinylpyrrolidone - 0.3-10; stearic acid and/or its salts - 0.5-1; lactose - the rest, and a coating that contains, wt %: titanium dioxide - 8-30; polyethylene glycol - 6-28; talc - 5-25; carmine - 0.3-2.5; yellow aluminium lake - 0.05-1; red aluminium lake - 0.01-0.5; quinoline yellow aluminium lake - 0.01-0.05; polyvinyl alcohol - the rest. There is also disclosed a method for preparing the presented solid dosage form.

EFFECT: preparation of the solid dosage form that exhibits the antiaggregatory activity.

7 cl, 2 tbl

Description

The invention relates to the pharmaceutical industry, namely to a solid dosage form for immediate release, with anti-aggregation effect, intended for the prevention of ischemic disorders in patients with atherosclerosis, and to a method for its preparation.

Clopidogrel - methyl (+) - (S) -α '- (o-chlorophenyl) - (6,7-dihydrothien [3,2-c] pyridin-5- (4H) acetate dihydrosulfate - inhibits platelet aggregation by inhibiting binding adenosine diphosphate (ADP) with receptors located on the surface of platelets and activation of the GP IIb / IIIa complex; inhibits ADP-dependent platelet aggregation. Clopid ogrel irreversibly alters platelet ADP receptors, and therefore platelets remain non-functional throughout life, and normal function is restored as the platelets are renewed.The time of onset of the effect is approximately one hour after administration (Encyclopedia of Medicines. 11th edition, M., radar-2004, p.441).

Clopidogrel is taken orally at 75 mg per day, regardless of food intake. Clopidogrel treatment should be started from a few days to 35 days in patients after myocardial infarction and from 7 days to 6 months in patients after ischemic stroke. In patients with acute coronary syndrome without ST segment elevation, treatment with clopidogrel should be started with a single dose of 300 mg, and then continued with a dose of 75 mg per day in combination with acetylsalicylic acid at a dose of 75-325 mg per day. Clopidogrel dose adjustment in elderly patients and patients with renal failure is not required. The duration of treatment with clopidogrel has not been established, but treatment regimens up to 12 months are used. The maximum effect is noted after 3 months of taking the drug.

When taken orally, clopidogrel is rapidly absorbed. The time to reach maximum serum concentration is reached approximately 1 hour after administration. Absorption is approximately 50% and is independent of food intake. The main part of clopidogrel and its main metabolite (respectively 98 and 94%) reversibly binds to plasma proteins. Clopidogrel is a prodrug. The active metabolite - the thiol derivative - is formed by the oxidation of clopidogrel to oxoclopidogrel with subsequent hydrolysis. This oxidation occurs with the participation of cytochrome P450. The active metabolite, which can be isolated in vitro, quickly and irreversibly binds to platelet receptors and inhibits their aggregation. It is not detected in blood serum. After a single or repeated administration with urine, 50% is excreted, and with feces - 46% of the administered dose of clopidogrel. The elimination half-life of the main metabolite after a single or repeated administration of clopidogrel is 8 hours.

Clopidogrel preparations are used for the prevention of ischemic disorders in patients with atherosclerosis (myocardial infarction, stroke, peripheral arterial thrombosis, sudden vascular death), including patients with ischemic stroke (from 7 days to 6 months), myocardial infarction (from several days to 35 days) after a heart attack), against the background of diagnosed diseases of the peripheral arteries, as well as in acute coronary syndrome (ACS) without raising the ST segment (unstable angina or myocardial infarction without Q wave) in combination with acetyls alicylic acid.

A known dosage form having anti-aggregation action, which contains clopidogrel and aspirin as active principles, as well as auxiliary substances such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like, while the tablets may be coated, for example, from sucrose (RU 2184547, 2002). A method of obtaining a known form includes mixing the active substances with auxiliary substances, tableting, after which a coating is applied. The disadvantages of the described dosage form, as well as the method of its manufacture, are that the core does not have high mechanical strength, as a result of which when coating is applied, problems arise in meeting the appearance of the product with the requirements.

The closest analogue of the claimed invention is a dosage form with anti-aggregation action and the method of its manufacture disclosed in patent RU 2303980, 2007. A known dosage form consists of a core containing in wt.%: Clopidogrel hydrosulfate - 44.0-65.0; milk sugar - 15.0-37.0; starch - 2.4-9.8; microcrystalline cellulose - 2.2-7.0; hydroxypropyl methylcellulose 0.3-0.8; polyethylene glycol - 1.5-4.0; magnesium stearate - 0.1-1.0; stearic acid - 0.1-1.0, and the shell containing in wt.%: hydroxypropyl methylcellulose - 58.0-72.0; polyethylene glycol - 13.5-20.5; titanium dioxide - 13.5-20.5; iron oxide red - 0.5-1.0. The tablets obtained according to the invention were dissolved at 94.1-96.4% in 30 minutes in an acidic medium.

The present invention is to obtain a solid dosage form of clopidogrel hydrosulfate in the form of tablets with high mechanical strength and at the same time rapid release of the active component. The rapid dissolution (high bioavailability) of the active substance of clopidogrel ensures a reduction in time before the onset of the therapeutic effect and is achieved by a carefully selected qualitative composition and quantitative ratio of auxiliary components.

The choice of target additives for the solid dosage form of clopidogrel hydrosulfate is complicated by the fact that this active pharmacological substance does not have good flowability, therefore, the dosage of the substance in the dosage form is uneven. In addition, clopidogrel hydrosulfate exhibits aggressive properties: when directly pressed, it adheres to the press tool, which leads to its corrosion.

In this regard, it is quite difficult to choose acceptable excipients for creating a dosage form of clopidogrel hydrosulfate that meets all the requirements of GP XI, in a simple way in hardware design.

The problem is solved in that the solid dosage form having anti-aggregation action consists of a core containing clopidogrel in the form of its pharmaceutical salt of hydrosulfate and auxiliary components - lactose, microcrystalline cellulose (MCC), talc, stearic acid and / or its salt and shell, while the core additionally contains sodium croscarmellose (primellose), low molecular weight polyvinylpyrrolidone (PVP) in the following ratio, wt.%:

Clopidogrel hydrosulfate 15-45 Microcrystalline cellulose 7-20 Talc 1-3 Croscarmellose Sodium 1-4 Low molecular weight polyvinylpyrrolidone 0.3-10 Stearic acid and / or its salts 0.5-1 Lactose Rest

and the shell contains polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc and dyes: carmine, yellow aluminum varnish, red aluminum varnish and quinoline yellow aluminum varnish, in the following ratio, wt.%:

Polyethylene glycol 6-28 Talc 5-25 Titanium dioxide 8-30 Carmine 0.3-2.5 Yellow aluminum varnish 0.05-1 Red aluminum varnish 0.01-0.5 Quinoline Yellow Aluminum Varnish 0.01-0.05 Polyvinyl alcohol Rest

In private embodiments of the invention, the problem is solved by the fact that the composition of the dosage form uses lactose of two brands - lactose "200 MESH" and lactose "Spraydray".

In private embodiments of the invention, the problem is solved in that for the preparation of the shell of the claimed dosage form, the finished powder system "Opadry II" is used.

The problem is also solved by a method for producing a solid dosage form, including wet granulation of a mixture of clopidogrel hydrosulfate powders and part of lactose with a pre-prepared aqueous solution of low molecular weight polyvinylpyrrolidone, drying of wet granulate, sieving and grinding, mixing the resulting product with the remaining part of lactose, MCC and sodium crushing a mixture of talc and stearic acid and / or its salts, tabletting while dedusting tablets and coating by spraying an aqueous suspension comprising polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, carmine, yellow aluminum varnish, red aluminum varnish and quinoline yellow aluminum varnish.

In private embodiments of the invention, the problem is solved in that during the first stage of the proposed method of wet granulation, a part of the lactose represented by the 200 MES brand is used, and in the second stage of the method, when mixing the product obtained in the first stage with the remaining auxiliary components, add lactose " Spraydray. "

The choice of acceptable target additives for the preparation of the pharmaceutical composition of clopidogrel hydrosulfate in solid dosage form is due not only to the compatibility of auxiliary components with the active substance, depriving the substance of its aggressive properties, achieving uniform dosage and molding of a solid tablet, but also achieving a high release rate of clopidogrel to ensure accessibility to suction.

The main excipients in the composition of the inventive solid dosage form are lactose and microcrystalline cellulose.

Form-forming substances have good flowability and compressibility, therefore, they create the necessary mass and volume and contribute to the preservation of a certain tablet shape.

Low molecular weight polyvinylpyrrolidone is used as a binder in solid dosage form.

The action of the binder is due to the ability to glue during the granulation of the auxiliary substances and the active component, which helps to keep individual particles together and the subsequent formation of granules, as a result, increase the strength of the tablets.

A mixture of formative substances and a binder component in higher quantitative ratios than stated does not provide a good release rate of the active substance, and in smaller proportions the stability and formative properties of the tablet are impaired.

Sodium croscarmellose (primellose) is used as a substance that provides rapid mechanical destruction of the tablet in a liquid medium, the speedy release of the active substance and its rapid absorption, and, consequently, the provision of a therapeutic effect.

The action of croscarmellose sodium as a disintegrant is due to the fact that due to its high absorption capacity it increases the porosity of the tablet due to the formation of hydrophilic pores, through which the liquid penetrates into the tablet and destroys it.

The presence of croscarmellose sodium in the claimed amount creates optimal conditions for penetration into the pores of the liquid and provides accelerated absorption of clopidogrel hydrosulfate. Croscarmellose sodium in higher quantitative ratios than stated does not provide the necessary release rate of the active substance, and in smaller proportions, the solubility of the tablet worsens and, as a result, reduces the release rate of the active substance.

Talc and stearic acid and / or its salts, preferably magnesium stearate, are used as a dusting agent that protects the press tool from sticking of the tablet mass onto the walls of the punches and dies and gives the tablet mass fluidity.

The use of stearic acid and / or its salt and talc in the declared amounts ensures uniform flow of the tablet mass from the hopper into the matrix, which ensures the accuracy of the dosage of the active substance, facilitates the easier ejection of the tablets from the matrix, prevents scratching on the faces of the matrices, and prevents the tablet mass from sticking to the walls punches and dies, as well as sticking particles together. In addition, moving substances remove the electrostatic charge from the particles of substances, which also improves their flowability.

Since stearic acid and its salts are hydrophobic substances, they impede the penetration of liquid into the porous structure of the tablet, which impairs its disintegration. Therefore, a larger than declared amount of these substances impairs the disintegration of the dosage form, and a smaller amount worsens the flowability.

Table 1 presents an example of the composition of the drug clopidogrel hydrosulfate in solid dosage form obtained according to the claimed invention.

Table 1 Name of substance Amount mg Core: 0.360 Clopidogrel hydrosulfate 0.097875 In terms of clopidogrel 0,07500 Lactose 0.169625 Low molecular weight polyvinylpyrrolidone 0.0185 Microcrystalline cellulose 0,0444 Talc 0.0111 Croscarmellose sodium (primrose) 0.0148 Stearic acid and / or its salts 0.0037 Shell "Opadry II85F34289": 0.010 Polyvinyl alcohol 0.004 Titanium dioxide 0,002418 Polyethylene glycol 0,00202 Talc 0,00148 Carmine 0.000054 Yellow aluminum varnish 0.000015 Red aluminum varnish 0.000008 Quinoline Yellow Aluminum Varnish 0.000005

An example embodiment of the invention by the claimed method of obtaining a solid dosage form is presented below.

The granulator is loaded with lactose "200 mesh" and clopidogrel hydrosulfate. The mixture of powders is mixed and moistened with a pre-prepared aqueous solution of low molecular weight polyvinylpyrrolidone while stirring, the mixture is wiped using a sieve with a hole diameter of 0.8-1.0 mm. The obtained granules are dried at a temperature of 45-50 ° C to a residual moisture content of not more than 2.0%. Then, the dried granules are subjected to a calibration process by sieving and grinding using sieves with a hole diameter of 0.5-0.8 mm.

At the second stage of the process, the resulting product is loaded into the mixer, lactose Spraydray, microcrystalline cellulose and croscarmellose sodium are added and the components are thoroughly mixed to achieve uniform distribution in the tablet mass and, as a result, dosing accuracy. For uniform distribution of bulk components, mixing in the second stage is carried out for 90 minutes

Then, talc and magnesium stearate are charged into the mixer. After mixing and dusting is completed, the resulting homogeneous tablet mass is sent to the tabletting step.

The mechanical strength of the tablet depends on the compression pressure applied during tabletting. According to the method, progressive pressing, i.e. growing gradually in a rotary tablet machine. Tableting is carried out with the dedusting of the resulting tablets.

The coating of the core tablets is carried out in a drum-type machine. A film-forming aqueous suspension, including polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, carmine, yellow aluminum varnish, red aluminum varnish and quinoline yellow aluminum varnish, is sprayed through nozzles onto tablets, which are simultaneously dried by a stream of warm air with constant stirring in a rotating perforated drum.

Table 2 shows the composition of the tablets within the stated intervals, which were subjected to research on indicators: disintegration, dissolution, strength, abrasion resistance, and storage stability.

table 2 Name of substance The composition of the composition,% one 2 3 four 5 6 7 Core: Clopidogrel hydrosulfate 45.0 15.0 26.45 26.45 26.45 26.45 26.45 Low molecular weight polyvinylpyrrolidone 0.3 0.5 0.5 0.5 0.5 10.0 0.5 Microcrystalline cellulose 12.0 12.0 7.0 20,0 12.0 12.0 12.0 Talc 3.0 3.0 3.0 1,0 3.0 3.0 3.0 Croscarmellose sodium (primrose) 4.0 1,0 4.0 4.0 1,0 4.0 4.0 Stearic acid and / or its salts 1,0 1,0 1,0 1,0 0.5 1,0 1,0 Lactose 34.7 67.5 58.05 47.05 56.55 43.55 53.05 Shell: Polyethylene glycol 6 28 20,2 20,2 20,2 20,2 20,2 Talc 25 5 14.8 14.8 14.8 14.8 14.8 Titanium dioxide 8 thirty 24.18 24.18 24.18 24.18 24.18 Carmine 0.3 2.5 0.54 0.54 0.54 0.54 0.54 Yellow aluminum varnish 0.05 one 0.15 0.15 0.15 0.15 0.15 Red
aluminum varnish 0.01 0.5 0.08 0.08 0.08 0.08 0.08 Quinoline Yellow Aluminum Varnish 0.01 0.05 0.05 0.05 0.05 0.05 0.05 Polyvinyl alcohol 68.63 32.95 40 40 40 40 40

All tablets had high solubility of the active substance (FSP norm - not less than 70% (Q) in 45 min) and tablet disintegration (FSP norm - not more than 30 min): formulation No. 1 - 99.6% with tablet disintegration during 8:45 min, recipe No. 2 - 99.1% for tablet disintegration for 8:57 min, recipe No. 3 - 98.9% for tablet disintegration for 8:51 min, recipe No. 4 - 99.5% for tablet disintegration within 8:50 min, formulation No. 5 - 99.3% with tablet disintegration within 8:52 min; Formulation No. 6 - 99.7% with tablet disintegration within 8:47 min; Formulation No. 7 - 99.2% with tablet disintegration within 8:48 min.

Tablets, the compositions of which are shown in table 2, have high strength and abrasion resistance:

compounding No. 1 strength - 65 N, abrasion resistance - 99.1%; Formulation No. 2 Strength - 67 N, abrasion resistance - 99.2%; compounding No. 3 strength - 69 N, abrasion resistance - 99.3%; Formulation No. 4 Strength - 70 N, abrasion resistance - 99.7%; Formulation No. 5 Strength - 68 N, abrasion resistance - 99.8%; Formulation No. 6 Strength - 70 N, abrasion resistance - 99.5%; Formulation No. 7 Strength - 69 N, abrasion resistance - 99.3%.

All formulations shown in table 2, showed stability during storage for 3 years.

Carefully selected qualitative composition and quantitative ratios of components determine the preparation of a solid dosage form of clopidogrel hydrosulfate that meets all the requirements of GP XI, its high technological effectiveness using available auxiliary substances, while ensuring a high disintegration rate and rapid release of the active substance from the tablet.

The present method provides the complete mechanization of the manufacturing process, its high productivity, the purity and hygiene of the tablets, the accuracy of the dosage and the speed of release of the active substance, good stability of the solid dosage form during storage.

Claims (7)

1. A solid dosage form having anti-aggregation activity, consisting of a core containing clopidogrel hydrosulfate as the active substance and target additives, including lactose, microcrystalline cellulose, talc, stearic acid and / or its salts, and shells, characterized in that the core is additionally contains sodium croscarmellose and low molecular weight polyvinylpyrrolidone in the following ratio, wt.%:
Clopidogrel hydrosulfate 15-45 Microcrystalline cellulose 7-20 Talc 1-3 Croscarmellose Sodium 1-4 Low molecular weight polyvinylpyrrolidone 0.3-10 Stearic acid and / or its salts 0.5-1 Lactose Rest,
and the shell contains polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, carmine, yellow aluminum varnish, red aluminum varnish and quinoline yellow aluminum varnish in the following ratio, wt.%:
Polyethylene glycol 6-28 Talc 5-25 Titanium dioxide 8-30 Carmine 0.3-2.5 Yellow aluminum varnish 0.05-1 Red aluminum varnish 0.01-0.5 Quinoline Yellow Aluminum Varnish 0.01-0.05 Polyvinyl alcohol Rest 2. The solid dosage form according to claim 1, characterized in that lactose 200 mesh and lactose Spraydray are used together as lactose. 3. The solid dosage form according to claim 1, characterized in that magnesium stearate is used as the salt of stearic acid. 4. The solid dosage form according to claim 1, characterized in that for the preparation of the shell using the powder system Opadry II. 5. The method of producing a solid dosage form according to claim 1, which consists in mixing the clopidogrel hydrosulfate powders and parts of lactose, moistening the resulting mixture with an aqueous solution of low molecular weight polyvinylpyrrolidone, drying the wet granulate, sieving and grinding, mixing the resulting product with the remaining part of lactose, microcrystalline cellulose and sodium croscarmellose, dusted with a mixture of talc and stearic acid and / or its salts, tablet with simultaneous dedusting of the obtained tablets, then tablets - cores are coated by spraying an aqueous suspension including polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, carmine, yellow aluminum varnish, red aluminum varnish and quinoline yellow aluminum varnish. 6. The production method according to claim 5, characterized in that the powders of clopidogrel hydrosulfate and lactose 200 mesh are mixed, moisten the resulting mixture with an aqueous solution of low molecular weight polyvinylpyrrolidone, dry wet granulate, sift and grind, mix the resulting product with lactose Sprayray, microcrystalline cellulose and , dusted with a mixture of talc and stearic acid and / or its salts, tableted with dedusting of the obtained tablets, then coated on the tablet cores by spray eniya aqueous suspension comprising polyvinyl alcohol, carmine, titanium dioxide, polyethylene glycol, talc, yellow aluminum lake, red aluminum lake and quinoline yellow aluminum lake. 7. The production method according to claim 5, characterized in that when tabletting, the method of progressive pressing is used.