RU2540519C2 - Dosage form of clopidogrel - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, particularly to pharmaceutical industry, and describes a dosage form of Clopidogrel presented in the form of a solid gelatine capsule. The dosage form contains Clopidogrel hydrogen sulphate, lactose anhydride, microcrystalline cellulose, sodium croscarmellose, colloidal silicon dioxide and magnesium stearate.

EFFECT: according to the invention, the dosage form of Clopidogrel contains a high amount of the active ingredient; it is prepared without the use of a wet granulation technique, and provides the more accurate dosage of the ingredients and the stability of the substances used.

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Description

The invention relates to medicine, in particular to the pharmaceutical industry, and can be used in the manufacture of solid dosage forms of drugs for the prevention and treatment of atherothrombotic conditions.

Atherothrombosis is recognized as the basis for the pathogenesis of most cardiovascular diseases. Various manifestations of atherothrombosis are the main cause of death in the population. According to the WHO, among 55694000 people who died on the planet in 2000, atterothrombosis accounted for 28.7%, infectious and parasitic diseases - 17.8%, cancer - 12.6%, injuries - 9.1%, lung diseases - 6% AIDS - 5.1%.

It was established that thrombosis is the cause of not only acute conditions, but also the progression of the disease. Thrombosis on the surface of the damaged atheroma occurs due to the activation of platelets and the coagulation cascade. The activation of the coagulation cascade is associated with the exposure of tissue factor on the surface of the atheroma, which, along with cholesterol and its esters, is contained in macrophages of the atherosclerotic plaque. Due to the activation of the coagulation cascade, thrombin is formed, a key coagulation enzyme.

In accordance with the recommendations of the National Society for Atherothrombosis (NOAT) and the All-Russian Scientific Society of Cardiology (GFCF), drugs that inhibit platelet function and coagulation cascade are theoretically justified for the prevention and treatment of all manifestations of atherothrombosis.

One of the agents related to thienopyridines, the mechanism of action of which is associated with the selective inhibition of adenine diphosphate (ADP) induced platelet aggregation, is clopidogrel. Clopidogrel has a better safety profile compared to ticlopidine (also applies to thienopyridines), and, in fact, replaced the latter in most clinical situations. Clopidogrel is rapidly absorbed and turns into an active metabolite - SR 26334 with a period of excretion from plasma of 8 hours. Against the background of regular administration of the drug, the suppression of platelet aggregation is enhanced, and 7 days after the drug is discontinued, it completely disappears.

In accordance with the above recommendations, clopidogrel, both as monotherapy and in combination with other agents, should be prescribed to patients with various atherothrombotic conditions and cardiovascular complications. So, clopidogrel therapy is indicated: for patients who have had acute coronary syndrome with an ST segment elevation on an ECG, regardless of whether they have been given thrombolytic therapy; patients with an established holometallic (without drug coating) stent (both with a high risk of bleeding and without it); patients with an installed stent secreting antiproliferative drugs (drug-eluting stent); patients with an installed stent and having absolute indications for taking vitamin K antagonists; in patients undergoing coronary bypass surgery due to acute coronary syndrome without ST elevation.

Thus, clopidogrel is quite effective and widely used in cardiology practice, indicated for use both as a therapeutic agent and for the prevention of cardiovascular diseases.

From the prior art, a solid dosage form (film-coated tablet) of clopidogrel is known (RF patent 2393862, publ. 07/10/2010) with the following ratio of components, 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

the shell contains the following ratio of components, 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

The specified dosage form is made as follows.

Clopidogrel hydrosulfate and lactose are mixed in a granulator and moistened with an aqueous solution of polyvinylpyrrolidone, after which the mixture is wiped, 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 granules are calibrated through a sieve with a hole diameter of 0.5- 0.8 mm, lactose, microcrystalline cellulose and sodium croscarmellose are added to the obtained granules and mixed, then talc and magnesium stearate are added to the mixture, after which the resulting mass is tabletted and film-coated.

Also known is the solid dosage form of clopidogrel (patent EA 015440 B1 publ. 30.10.2009), which contains, relative to its total weight, 20-40 wt.% The polymorphic form of clopidogrel hydrosulfate and excipients. This dosage form is a tablet, film-coated tablet or capsule.

These known dosage forms and formulations have a number of significant drawbacks that impede the process of their production, increase the wear of equipment and reduce the quality of the active substance due to mechanical and thermal effects (pressing, granulation, drying, coating), as well as the inclusion of a significant amount of auxiliary substances, not having a therapeutic effect.

Clopidogrel hydrosulfate powder, like many pharmaceutical substances, has a small particle size and low residual moisture and, therefore, does not have sufficient flowability and compactability for the manufacture of solid dosage forms by direct compression. Specialists in this field it is clear that in the manufacture of a solid dosage form of a powder having such properties, granulation or the introduction of a large number of auxiliary substances of special grades into the mixture is required.

However, granulation is an undesirable process, because the product is exposed to granulating liquid and elevated temperature during drying, which negatively affects the stability of the active principle. This process significantly complicates the production, since it requires the use of special equipment and the introduction of a large number of auxiliary substances into the mixture, which is economically impractical.

Known dosage forms of clopidogrel in the form of tablets for masking negative organoleptic properties require coating, which is also a laborious, costly process, during which the surface of the tablet is subjected to additional exposure to negative physical factors - solvents and elevated temperature.

When exposed to elevated temperature, there is a risk of decomposition of part of the active substance with the formation of impurities. The thermolability of clopidogrel hydrosulfate is confirmed by its special storage conditions recommended by the manufacturer. So in the pharmacopeia article, the storage temperature is recommended from +2 to + 8 ° C.

In addition, the prior art solid dosage form of clopidogrel, made in the form of a capsule (patent EA 015440 B1, publ. 30.10.2009), in connection with the properties of the active pharmaceutical substance requires the introduction of a significant amount of excipients, which significantly increases the total weight of the pharmaceutical composition . The range of active substance values declared by the authors of the said patent from 20 to 40 wt.% And the feasibility of manufacturing a pharmaceutical composition with a dosage of at least 75 mg of clopidogrel base (minimum daily single dose), which corresponds to 97.88 mg of clopidogrel hydrosulfate, in the case of the minimum declared content (20 %), involves the manufacture of capsules with a content weight of about 500 mg. Reception of capsules of such a mass seems difficult for the patient, especially in advanced and senile age.

Thus, at present, there is a need to develop clopidogrel preparations that are more optimal in size and weight, affordable and easy to manufacture, characterized by high chemical and physical stability during storage, meeting modern quality requirements for solid dosage forms, the qualitative and quantitative composition of which will provide high manufacturability with a simultaneous low cost of production, while devoid of the disadvantages of existing tablets and capsules OF DATA dosage forms, as well as broaden the arsenal of anti-thrombotic drugs and antiaggregation of domestic production.

The technical task of the invention is the creation of a solid oral dosage form of clopidogrel, which provides a high quantitative content of the active active ingredient, the minimum amount of excipients in the mass and the accuracy of their dosage, with high bioavailability, reduced wear of equipment during its manufacture, as well as providing conditions for long-term preservation of chemical properties of the starting materials used in production by improving the quality characteristics of radiated products.

The technical result of the invention is to reduce the mass of the solid dosage form, increase the amount of active active substance and reduce the amount of excipients, improve bioavailability, uniformity and accuracy of dosage, as well as provide conditions for maintaining and stability of the chemical properties of the active pharmaceutical substance during long-term storage.

It is proved that the method for producing dosage forms largely determines the stability of the drug, its release rate from the dosage form, absorption rate and, ultimately, therapeutic efficacy. To achieve a technical result and taking into account the features and properties of an active pharmaceutical substance, the authors of the present invention decided to use hard gelatin capsules as a dosage form, and the components of the composition and method of manufacturing the capsules were selected. The choice of this dosage form and composition allows you to most fully and efficiently achieve the specified technical result, since the substances remain unchanged without being subjected to wet granulation, heat and pressure, as in the case of tablet production. In addition, gelatin is a product of partial hydrolysis of collagen, which forms the main part of the connective tissue of vertebrates. The protein molecule of gelatin is based on a polypeptide chain formed by 19 amino acids; most of them are indispensable for humans. The main ones are: glycine, proline, hydroxyproline, glutamic acid, arginine, lysine. Gelatin is easily and quickly absorbed even in severe gastrointestinal disorders, is non-toxic and has no adverse reactions (Industrial technology of drugs: [Textbook. In 2 volumes. Volume 2 / V.I. Chueshov, M.Yu. Chernov, L.M. Khokhlova et al.]; Edited by Professor V.I. Chueshov. - Kharkov: MTK-Kniga; Publishing House of the NFAA, 2002. - 716 p.; P. 396).

Most preferred is the following number of components in the contents of the capsule in wt.%:

The composition of the components per 1 capsule % Clopidogrel hydrosulfate 40.0-60.0 Lactose anhydride 54.3-11.0 Microcrystalline cellulose 5.0-14.0 Croscarmellose sodium 0.5-10.0 Silicon Colloidal Dioxide 0.1-3.0 Magnesium stearate 0.1-2.0 Total: 100.0

The indicated content of agglomerated anhydride lactose is due to the need to impart fluidity to the mixture, and also, apparently, the presence of this component does not allow the mixture to separate into fractions due to the adhesion of small particles.

The introduction of microcrystalline cellulose in an amount of 5-15% softens the automatic dosing process. In addition, cellulose is able to conduct moisture inside the product, which allows to obtain improved characteristics in determining the dissolution of the drug.

Croscarmellose sodium particles swell when wet. This phenomenon is used to regulate the disintegration time of the dosage form.

The introduction of colloidal dioxide and magnesium stearate into the composition of silicon, as antifriction substances, slightly increases the fluidity of the mixture and reduces friction between the product and the contacting surfaces of the equipment, thereby contributing to increased productivity and reduced wear of the latter.

Standard hard gelatine capsules are commonly used in production. The average weight of the contents of the capsule depends on the size of the capsule and the geometric parameters of the dosage disk and can range from 160 to 250 mg.

The specified technical result is achieved due to the fact that the suspended clopidogrel hydrosulfate, lactose anhydride, microcrystalline cellulose, croscarmellose sodium, silicon dioxide colloidal and magnesium stearate are mixed in a drum type mixer, then calibrated on a vertical granulator, after which the resulting mixture is metered in a disk method and hard gelatin capsules.

Tables 1-6 show options for formulations of the claimed composition.

To confirm the indicated technical result, in accordance with the requirements of the General Pharmacopoeia Monograph 42-0003-04, stability studies were carried out using the “accelerated storage” method and the dissolution kinetics after long-term storage, quantitative content and uniformity of dosage.

The study of the stability of the capsules was carried out by the method of “accelerated aging” in a blister strip packaging. Samples were stored at 55 ° C. The research results of various variants of the formulations of the claimed composition are shown in table 7. The sum of the decomposition products, according to the tests, is less than 0.35%.

To assess dissolution, a “paddle mixer” type apparatus was used. The rotation speed of the blades is 50 rpm; the dissolution medium is 0.1 M hydrochloric acid solution, the volume of the dissolution medium is 900 ml, the dissolution time is 30 minutes The number of capsules tested for each formulation is 6.

Table 8 shows the results of the study of the kinetics of dissolution after 138 days of storage under accelerated aging, the average value for 6 capsules, in% of the nominal amount of clopidogrel.

The data shown in table 8 indicate a high rate of transition of the active substance from the dosage form to the solution. The dissolution rate after long-term storage after 15 minutes is about 95% or more.

A capsule disintegration study was also conducted. The process of determining the disintegration of the capsules was carried out in accordance with the article of the Global Fund XI, issue 2, p. 143. This article states that capsules should disintegrate in a time not exceeding 20 minutes. Disintegration of clopidogrel capsules was observed for all variants after 10-12 minutes.

Determination of dosage uniformity was carried out in accordance with GF XI, issue 2, p. 144. The study was conducted for each formulation of the claimed composition (options 1-6).

Table 9 shows the results of maximum deviations from the claimed amount of the active substance in each of the formulations.

The maximum deviations from the expected content were ± 2.4%, which is much better than the requirements of the leading Pharmacopoeias, which allow a deviation of up to 15%.

A method of manufacturing a dosage form in the form of a capsule containing the above substances, consists of the following steps; all components are loaded into a drum type mixer in the following sequence: lactose anhydride, clopidogrel hydrosulfate, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose; then stirred in the specified mixer for 2 minutes at a speed of 10 rpm, after which additionally mix for 2 minutes at a speed of 15 rpm; then calibrate the mixture on a vertical granulator through a 1.0 mm mesh, with washers 16-17 mm and a speed of 4-5 units; the resulting mixture is dispensed in a disk manner into capsules on an automatic capsule filling machine. Productivity in this case is about 50,000 pieces of capsules per hour.

As a result, the selection of the ratio of the components of the formulation and the use of a hard gelatin capsule as a dosage form containing clopidogrel allows achieving the indicated technical result when a relatively small (from 40 to 60%) amount of excipients is introduced into the composition without exposing the chemicals to the negative effects of moisture, heat (drying) and pressing, preserving their initial properties, ensuring uniformity of dosage within ± 2.4% and high bioavailability of substances, as well as optimal lovia for their preservation. The specified method of manufacturing clopidogrel capsules also provides high performance and minimal wear on the equipment.

Table 1 Recipe Option No. 1 Components Recipe mg / caps. % Clopidogrel hydrosulfate 97.88 * 54.38 Lactose anhydride 58.00 32.22 Microcrystalline cellulose 17.00 9.44 Croscarmellose sodium 3.52 1.96 Silicon Colloidal Dioxide 1.80 1.00 Magnesium stearate 1.80 1.00 The mass of the contents of the capsule: 180.00 100.00 * in terms of clopidogrel 75.0 mg

table 2 Recipe # 2 Components Recipe mg / caps. % Clopidogrel hydrosulfate 100.00 40.00 Lactose anhydride 135.75 54.30 Microcrystalline cellulose 12.50 5.00 Croscarmellose sodium 1.25 0.50 Silicon Colloidal Dioxide 0.25 0.10 Magnesium stearate 0.25 0.10 The mass of the contents of the capsule: 250.00 100.00

Table 3 Recipe Option No. 3 Components Recipe mg / caps. % Clopidogrel hydrosulfate 96.00 60.00 Lactose anhydride 17.60 11.00 Microcrystalline cellulose 22.40 14.00 Croscarmellose sodium 16.00 10.00 Silicon Colloidal Dioxide 4.8 3.00 Magnesium stearate 3.20 2.00 The mass of the contents of the capsule: 160.00 100.00

Table 4 Recipe number 4 Components Recipe mg / caps. % Clopidogrel hydrosulfate 100.00 40.00 Lactose anhydride 113.75 45.50 Microcrystalline cellulose 25.00 10.00 Croscarmellose sodium 6.25 2,50 Silicon Colloidal Dioxide 2,50 1.00 Magnesium stearate 2,50 1.00 The mass of the contents of the capsule: 250.00 100.00

Table 5 Recipe number 5 Components Recipe mg / caps. % Clopidogrel hydrosulfate 96.00 60.00 Lactose anhydride 32.00 20.00 Microcrystalline cellulose 8.00 5.00 Croscarmellose sodium 16.00 10.00 Silicon Colloidal Dioxide 4.80 3.00 Magnesium stearate 3.20 2.00 The mass of the contents of the capsule: 160.00 100.00

Table 6 Recipe # 6 Components Recipe mg / caps. % Clopidogrel hydrosulfate 99.00 55.00 Lactose anhydride 54.54 30.30 Microcrystalline cellulose 25,20 14.00 Croscarmellose sodium 0.90 0.50 Silicon Colloidal Dioxide 0.18 0.10 Magnesium stearate 0.18 0.10 The mass of the contents of the capsule: 180.00 100.00

Table 7 The total content of decomposition products in the study of stability Recipe Option No. The amount of impurities at different storage periods 0 days 23 days 46 days 69 days 92 days 115 days 138 days one 0.015 0.024 0.04 0.11 0.25 0.29 0.32 2 0.02 0,035 0.08 0.15 0.20 0.25 0.30 3 0.009 0,025 0,045 0.2 0.25 0.3 0.33 four 0.005 0.01 0.02 0.05 0.1 0.15 0.25 5 0.01 0.02 0.06 0.15 0.23 0.27 0.3 6 0.007 0.015 0.05 0.1 0.15 0.2 0.25

Table 8 Average dissolution kinetics for various formulations Clopidogrel hydrosulfate,% Recipe Option No. 5 minutes 10 min 15 minutes 30 minutes one 78.95 90.35 96.30 97.50 2 76.80 86.50 94.85 95.25 3 79.90 93.60 97.15 98.75 four 78.50 89.90 95.30 96.95 5 81.50 92.45 97.90 98.95 6 75.70 86.10 94.20 94.90

Table 9 Maximum deviations from the amount of active substance claimed in the formulation. Recipe Option No. Maximum deviation,% one + 2.10 / -1.50 2 + 1.90 / -2.40 3 + 2.10 / -1.85 four + 2.20 / -2.25 5 + 2.35 / -1.75 6 + 1.85 / -2.30

Claims (1)

The dosage form of clopidogrel, made in the form of a hard gelatin capsule, including clopidogrel hydrosulfate, microcrystalline cellulose, colloidal silicon dioxide, characterized in that it additionally contains lactose anhydride, croscarmellose sodium and magnesium stearate, with the following components in wt.%:
Clopidogrel hydrosulfate 40.0-60.0 Lactose anhydride 54.3-11.0 Microcrystalline cellulose 5.0-14.0 Croscarmellose sodium 0.5-10.0 Silicon Colloidal Dioxide 0.1-3.0 Magnesium stearate 0.1-2.0