Dosage form of clopidogrel

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.

9 tbl


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.

Aerodromes recognized as the basis of the pathogenesis of most cardiovascular diseases. The various manifestations of atherothrombosis are the leading cause of death in the population. According to who among 55694000 people who died on the planet in 2000 to aerodromes accounted for 28.7% infectious and parasitic diseases at 17.8%, cancer - 12,6%, injuries by 9.1%, lung disease (6%), AIDS - 5,1%.

Found that thrombus formation is the cause not only acute conditions, but also the progression of the disease. Thrombus formation on the surface of the damaged atheroma occurs due to activation of platelets and the coagulation cascade. Activation of the coagulation cascade is associated with the exposure on the surface of the atheroma tissue factor contained, along with cholesterol and its esters in macrophages of atherosclerotic plaques. Due to the activation of the coagulation cascade is formed thrombin is a key enzyme of blood coagulation.

In accordance with the recommendations of the National society for atherothrombosis (NOT) and all-Russian scientific society of cardiology (GFCF) for the prevention and treatment of all p is oyavleniy of atherothrombosis theoretically warranted drugs inhibiting the function of platelets and the coagulation cascade.

One means relating to thienopyridines, mechanism of action which is associated with selective inhibition adeninivorans (ADP) induced platelet aggregation, is clopidogrel. Clopidogrel has a better safety profile compared with ticlopidine (also applies to thienopyridines), and virtually replaced the latter in most clinical situations. Clopidogrel is rapidly absorbed and transformed into an active metabolite SR 26334 with the period of excretion of plasma equal to 8 hours. On the background of regular drug inhibition of platelet aggregation is enhanced, and 7 days after withdrawal of the drug disappears completely.

In accordance with the above recommendations clopidogrel, both as monotherapy and in combination with other drugs should be administered to patients with various atherothrombotic conditions and cardiovascular complications. So, therapy clopidogrel shown: patients who had acute coronary syndrome with ST segment elevation on ECG, regardless, have you done any of them thrombolytic therapy; patients with established observed with bare metal (without drug coverage) of the stent (as with high risk of bleeding, and without it); patients with mounted stent emitting antipole erative medications (drug-eluting stent); patients with mounted stent and having absolute indications for the reception of the vitamin K antagonists; in patients undergoing coronary artery bypass surgery due to acute coronary syndrome without ST elevation.

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

From the prior art known solid dosage form (tablet film coated liner) clopidogrel (RF patent 2393862, publ. 10.07.2010) with the following ratio of components, wt.%:

Clopidogrel the hydrosulfate15-45
Microcrystalline cellulose7-20
Sodium croscarmellose1-4
The low-molecular polyvinylpyrrolidonethe 0.3-10
Stearic acid and/or its salts0,5-1

the wrapper contains the following ratio of components, wt.%:

The polyethylene glycol6-28
Titanium dioxide8-30
Yellow aluminum lacquer0,05-1
Red aluminum lacquer0,01-0,5
Quinoline yellow aluminium painted0,01-0,05
Polyvinyl alcohol:rest

Specified dosage form is manufactured by the following method.

Clopidogrel the hydrosulfate and lactose are mixed in a granulator and hydrate aqueous solution of the polyvinylpyrrolidone, and then wipe the mixture 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 the hole diameter of 0.5-0.8 mm, the resulting granules add lactose, microcrystalline cellulose and sodium croscarmellose and mixed, then the mixture was added talc and magnesium stearate, the donkey and the resulting mass tabletirujut and cover film cover.

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

These known dosage forms and formulations have a number of significant shortcomings that hinder the process of their production, increase wear and reduce the quality characteristics of the active substance due to mechanical and temperature effects (extrusion, granulation, drying, coating), as well as the inclusion of substantial amounts of auxiliary substances that do not have a therapeutic effect.

Powder clopidogrel the hydrosulfate, like many pharmaceutical substances, has a small particle size and low residual moisture and, therefore, does not have sufficient flowability and the ability to seal for the manufacture of solid dosage forms by direct pressing. Specialists in this field it is clear that in the manufacture of solid dosage form of powder having such properties requires granulation or introducing a mixture of a number of excipients special marks./p>

However, the granulation is an undesirable process, because the product is subjected to granulating liquid and high temperatures, which affects the stability of the current beginning. This process complicates the production, because it requires the use of special equipment and the introduction of a mixture of a number of auxiliary substances, that is economically impractical.

Known dosage forms clopidogrel in the form of tablets to mask the negative organoleptic properties require coating, which is also time-consuming, costly process in which the surface tablet is an additional negative impact of physical factors - solvents and high temperatures.

When exposed to high temperatures there is a risk of decomposition of the active substance with the formation of impurities. thermolability of clopidogrel hydrosulfate is confirmed by its special storage conditions recommended by the manufacturer. So in the Pharmacopoeia requirements recommended storage temperature from +2 to +8°C.

In addition, known from the prior art solid dosage form for clopidogrel made in the form of capsules (patent EA 015440 B1, publ. 30.10.2009), in connection with the properties of the active formats ticheskoj substance requires the introduction of significant amounts of auxiliary substances, which significantly increases the total weight of the pharmaceutical composition. Claimed by the authors of the said patent, the interval of values of the active substance from 20 to 40 wt.% and the feasibility of manufacturing the pharmaceutical composition dosage of 75 mg of clopidogrel base (minimum daily single dose), which corresponds to 97,88 mg of clopidogrel hydrosulfate, if the minimum of the declared content (20%), involves making capsules with a mass content of about 500 mg. capsules of such weight it is difficult for patients, especially in elderly and senile age.

Thus, currently, there is a need to develop a more optimal size and weight, affordable, and simple to manufacture drugs for clopidogrel with high chemical and physical stability when stored in accordance with modern quality requirements for solid dosage forms, the qualitative and quantitative composition which will provide high technology with concurrent low production cost, devoid of the shortcomings of the existing tablet and capsule dosage forms, as well as broaden the Arsenal of antithrombotic and antiaggregatory agents of domestic production.

Technical adaca of the claimed invention is to provide a solid they orally dosage forms clopidogrel, providing high quantitative content of the active substance, the minimum number of auxiliary substances in the weight and accuracy of dosing with high bioavailability, reduced equipment wear in its manufacture, as well as providing favourable conditions for long-term preservation of the chemical properties of the original substances used in the production of the improvement of qualitative characteristics of the products obtained.

The technical result of the invention is the reduced mass of solid dosage forms, the increase in the number of active substances and the reduction in the number of auxiliary substances, improve bioavailability, uniformity and accuracy of dosing, as well as providing conditions for the preservation and stability of the chemical properties of the active pharmaceutical substance during prolonged storage.

It is proved that the method of obtaining the dosage forms largely determines the stability of the drug, the rate of its release from the dosage form, the intensity of the suction and ultimately therapeutic efficacy. To obtain a technical result and taking into account the characteristics and properties of the active pharmaceutical substances, the authors of the present invention, it was decided to use as a medicinal F. RMI hard gelatin capsules, and was the selection of the components and method of manufacture of the capsules. The choice of this pharmaceutical form and composition allows to fully and efficiently to achieve the technical result, as substances remain unchanged, without wet granulation, heat and pressure, as in the case of the production of tablets. In addition, gelatin is a product of partial hydrolysis of collagen, which forms the main component of the connective tissue of vertebrates. In the basis of the protein molecule of gelatin lies 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 absorbed even in severe disorders such as gastro-intestinal, non-toxic and has no adverse reactions (Industrial technology of drugs: [Tutorial. 2 so That 2 / Century And. Chueshov, M. Y. Chernov, L. M. Khokhlov and others]; edited by Professor C. I. Chueshov. - Kharkov: MTK-Book; the Publisher of PAU, 2002. - 716 S.; S. 396).

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

Components 1 capsule%
The bedbug who has dogrel the hydrosulfate 40,0-60,0
Lactose anhydride54,3-11,0
Microcrystalline cellulose5,0-14,0
Croscarmellose sodium0.5 to 10.0
Colloidal silicon dioxide0,1-3,0
Magnesium stearate0,1-2,0

The specified content of the agglomerated lactose anhydride due to the need to give a mixture of fluidity and, apparently, it is the presence of this component does not allow to split the mixture into fractions due to the adhesion of small particles.

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

Particle croscarmellose sodium swell upon hydration. This phenomenon is used for the regulation time raspadaemosti dosage forms.

Introduction to the composition of the colloidal silicon dioxide and magnesium stearate as anti-friction substances, NESCO who are increases the fluidity of the mixture and reduces the friction between product and product contact surfaces of equipment, thereby increasing performance and reducing wear of the latter.

In the production of commonly used standard hard gelatin capsules. The average weight of the contents of the capsules depends on the size of the capsule and geometrical parameters of the dosing disk and can range from 160 to 250 mg.

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

In tables 1-6 variants of formulations of the claimed composition.

To confirm the technical result, in accordance with the requirements of the CFC 42-0003-04 were conducted stability studies by the method of "rapid storage" and dissolution kinetics after long-term storage, the concentration and uniformity of dosage.

The study of the stability of the capsules was performed by the method of "accelerated aging" in blister packaging. Storage of the samples was carried out at a temperature of 55°C. the Results of studies of various formulations Appl the frame of the composition shown in table 7. The amount of decomposition products according to performed tests, is less than 0.35%.

To assess the dissolution of the used device type Blade mixer". The blade rotation speed of 50 rpm; the medium dissolution of 0.1 M hydrochloric acid solution, the volume of environment dissolution of 900 ml, dissolution - 30 min. Number of capsules tested, for each version of the recipe - 6 pieces.

Table 8 presents the results of studies of the kinetics of dissolution after 138 days of storage under conditions of accelerated aging, the average value of 6 capsules, % of the nominal amount of clopidogrel.

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

Also conducted research raspadaemosti capsules. The process of determining raspadaemosti capsules was conducted in accordance with article GF XI, vol.2, page 143. This article States that capsules should decay over time not exceeding 20 minutes Raspadaemost capsules clopidogrel was observed for all variants 10-12 minutes

The definition of uniformity of dosing was performed in accordance with the global Fund XI, vol.2, page 144. The study was performed for each of the formulations of the claimed composition (in the options 1-6).

Table 9 shows the results of maximum deviations from the declared quantity of the active substance in each of the variants of the recipe.

Maximum deviations from the expected content was ±2.4%, which is significantly better than the requirements of major Pharmacopoeias, allowing a deviation of up to 15%.

The method of manufacture of the dosage form in the form of capsules containing the above substances, consists of the following steps; all the components are loaded into the drum-type mixer in the following sequence: lactose anhydride, clopidogrel the hydrosulfate, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose; then mix in the specified mixer for 2 min with a speed of 10 rpm, and then additionally stirred for 2 min with a speed of 15 rpm; then calibrated mixture on a vertical granulator through a grid of 1.0 mm, washers 16-17 mm and the speed of 4-5 units; the resulting mixture is metered disk method in capsules on automatic machine for filling capsules. The performance is about 50,000 pieces of capsules per hour.

In the selection of the ratio of ingredients and the use of hard gelatin capsules as a dosage form containing clopidogrel, allows to achieve the specified technical result is ATA, with the introduction of a relatively small, from 40 to 60%, the number of auxiliary substances without chemical substances adverse effects of moisture, heat (drying) and pressing, preserving their original properties, ensuring uniformity of dosing within ±2.4% and high bioavailability of substances, as well as optimal conditions for their preservation. The specified method of manufacturing a capsule clopidogrel also provides high performance and minimum wear.

Table 1
Variant formulations No. 1
Clopidogrel the hydrosulfate97,88*54,38
Lactose anhydride58,0032,22
Microcrystalline cellulose17,009,44
Croscarmellose sodium3,521,96
Colloidal silicon dioxide1,801,00
Magnesium stearate1,801,00
The weight of the contents of the capsules:180,00100,00
* in terms of clopidogrel 75,0 mg

Table 2
Variant formulation No. 2
Clopidogrel the hydrosulfate100,0040,00
Lactose anhydride135,7554,30
Microcrystalline cellulose12,505,00
Croscarmellose sodium1,250,50
Colloidal silicon dioxide0,25 0,10
Magnesium stearate0,250,10
The weight of the contents of the capsules:250,00100,00

Table 3
Variant formulation No. 3
Clopidogrel the hydrosulfate96,0060,00
Lactose anhydride17,6011,00
Microcrystalline cellulose22,4014,00
Croscarmellose sodium16,0010,00
Colloidal silicon dioxide4,83,00
Magnesium stearate3,202,00
The weight function is wow capsules: 160,00100,00

Table 4
Variant formulation No. 4
Clopidogrel the hydrosulfate100,0040,00
Lactose anhydride113,7545,50
Microcrystalline cellulose25,0010,00
Croscarmellose sodium6,252,50
Colloidal silicon dioxide2,501,00
Magnesium stearate2,501,00
The weight of the contents of the capsules:250,00100,00

Table 5
Variant formulation No. 5
Clopidogrel the hydrosulfate96,0060,00
Lactose anhydride32,0020,00
Microcrystalline cellulose8,005,00
Croscarmellose sodium16,0010,00
Colloidal silicon dioxide4,803,00
Magnesium stearate3,202,00
The weight of the contents of the capsules:160,00100,00

Table 6
Variant formulation No. 6
Components Recipe
Clopidogrel the hydrosulfateto 99.0055,00
Lactose anhydride54,5430,30
Microcrystalline cellulose25,2014,00
Croscarmellose sodium0,900,50
Colloidal silicon dioxide0,180,10
Magnesium stearate0,180,10
The weight of the contents of the capsules:180,00100,00

Table 7
The total content of decomposition products in the stability studies
Variant formulations No.The amount of impurities at different periods of storage
0 days 23 days46 days69 days92 days115 days138 days
50,010,020,060,15 0,230,270,3

Table 8
The average dissolution kinetics for different recipes
Clopidogrel the hydrosulfate, %
Variant formulations No.5 min10 min15 min30 min
478,50 89,9095,3096,95

Table 9
The maximum deviation from the inventive formulation amount of the active substance.
Variant formulations No.The maximum deviation, %

Dosage form clopidogrel made in the form of hard gelatin capsules, comprising clopidogrel the hydrosulfate, microcrystalline cellulose, silicon dioxide number is oigny, characterized in that it further contains lactose anhydride, croscarmellose sodium and magnesium stearate, in the following components in wt.%:

Clopidogrel the hydrosulfate40,0-60,0
Lactose anhydride54,3-11,0
Microcrystalline cellulose5,0-14,0
Croscarmellose sodium0.5 to 10.0
Colloidal silicon dioxide0,1-3,0
Magnesium stearate0,1-2,0


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FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a solid pharmaceutical product for oral administration which contains a photosensitiser representing a compound of general formula I:

wherein R1 represents a substituted or unsubstituted unbranched, branched or cyclic alkyl group, and each R2 independently represents a hydrogen atom or optionally a substituted alkyl group or its pharmaceutically acceptable salt, and at least one pharmaceutically acceptable carrier or excipient. The above pharmaceutical product is presented in the form of a tablet, a pill or a capsule having an enteric and gastroresistant coating, or in the form of the tablet or the capsule containing a number of balls, drops, granules or mini-pills with an enteric and gastroresistant coating. The above coating disintegrates in the lower gastrointestinal tract. The invention also refers to using the above photosensitiser in preparing the solid pharmaceutical product applicable in photodynamic treatment or diagnostics of a cancer condition in the lower gastrointestinal tract. What is also described is a photodynamic method of treating or diagnosing the cancer condition in the lower gastrointestinal tract by administering the solid pharmaceutical product containing the photosensitiser.

EFFECT: invention provides photosensitiser delivery to the lower gastrointestinal tract, and homogenous distribution of the photosensitiser in the target region, thereby improving the response to photodynamic treatment or diagnostics.

20 cl, 2 dwg, 2 tbl, 54 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the field of cosmetology, namely to a cosmetic composition for peroral introduction, which contains a combination of lycopene, vitamin C, vitamin E and at least one polyphenol compound, obtained from pine bark, in which the ratio of weight content of polyphenol compound to the sum of weight contents of lycopene, vitamin C and vitamin E constitutes from 0.3 to 0.7, as s single active ingredient.

EFFECT: invention is intended for prevention and/or treatment of wrinkles in the area of eyes and mouth angles, small wrinkles, eye bags and dark circles under eyes.

22 cl, 2 ex, 11 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and represents a controlled-release aceclofenac preparation for oral administration once a day, exhibiting the fast analgesic and anti-inflammatory action, containing a fast-release layer containing aceclofenac, a solubiliser, a water-soluble additive, a disintegrating agent, a vehicle and a fast-acting additive, as well as a sustained-release layer containing aceclofenac, a solubiliser and a release control base consisting of mixture of hydroxypropyl methyl cellulose (HPMC) with a viscosity of 80,000 sP to 120,000 sP and carbomer taken in mass ratio 7:1 to 9:1.

EFFECT: invention provides a sequential and uniform dissolution rate and a controlled release of the active agent.

7 cl, 12 tbl, 11 dwg, 10 ex