Pharmaceutical solid composition on the basis of enalapril maleate and its preparation

 

(57) Abstract:

The pharmaceutical composition contains as the active compounds of enalapril maleate and as an auxiliary inert substances lactose, starch, polyvinylpyrrolidone, calcium stearate or magnesium and talc in certain quantities. In the production method of the pharmaceutical composition on the basis of enalapril maleate in the form of tablets by wet granulation using a moisturizing tableting mass combined humidifier. The humidifier contains 2-4% solution of starch paste and 15-20% aqueous solution of polyvinylpyrrolidone. Pharmaceutical solid composition on the basis of enalapril maleate satisfies all the requirements of the pharmaceutical standard raspadaemosti, solubility and stability during storage. Use as part of a combined humidifier aqueous solution of polyvinylpyrrolidone leads to lower cost tablets. 2 S. and 2 C.p. f-crystals.

The invention relates to medicine, more precisely to the pharmacy, and can be used for the preparation of solid pharmaceutical compositions, the active compound which is enalapril maleate.

Enalapril maleate is otteni and heart failure in the inhibitory effect on the renin - angiotensin - aldosterone system.

The drug most often injected in the gastrointestinal tract through the mouth (peros). The advantage of this way is easy to use as it does not require the help of medical staff, as well as comparative safety and absence of complications specific for parenteral administration.

When administered orally, the drug must pass through a series of biological cell membranes (mucous membrane of the stomach, liver and so on) and only part of it gets into the blood system. The effect of the drug depends largely on how big this part. This indicator characterizes the bioavailability of the drug. The bioavailability of a drug is influenced not only by the route of administration of the drug, but biopharmaceutical factors (dosage form, its composition, characteristics of the production technology of the drug).

After oral administration enalapril absorbed in the gastrointestinal tract and as a result of deesterification during the hydrolysis in the liver becomes active metabolite enalaprilat. Under the action of the drug decreases peripheral resistance arteries. In heart nedostatocnosti hydrolyzed with the formation of active connections enalaprilat, inhibition angiotensinase enzyme.

Among the variety of different pharmaceutical compositions on the basis of enalapril maleate, convenience and ease of use definitely produce solid dosage forms, therefore research and development of compounds to solid pharmaceutical compositions on the basis of enalapril maleate continue until the present time.

Mostly solid dosage forms for oral administration comprise one or more pharmaceutically active compounds and auxiliary inert substances, including solvents, fillers, diluents, preservatives and stabilizers, binders and sliding substances, flavorings, and which largely determine the rate of release of pharmaceutically active compounds, the speed and completeness of their absorption, as well as the stability and strength of the dosage form.

Known for solid dosage forms based enalapril used as antihypertensive drugs, for example EDNIT (see "journal of pharmacy", 1,1999,, S. 46).

Known for solid dosage forms on the basis of enalapril, for example ENAP N, containing 0.01 g (10 mg) analysed (see Mashkovsky M. D. Medicines. Manual for doctors. 14th edition, revised, corrected and augmented. M: New wave, 2000, volume 1, S. 422-423).

Known solid dosage form of enalapril and its preparation (see Russian Federation patent 2165251, class a 61 K 9/20, a 61 P 9/12, the filing date 06.09.2000,, date of publication 27.02.2000, the applicant: Federal state unitary enterprise Moscow industrial chemical-pharmaceutical join them. N. A. Semashko).

Known solid dosage form contains as the active compounds of enalapril maleate and auxiliary inert substances in the following ratio, wt.%:

Enalapril maleate - 4,5-5,5

Sodium bicarbonate - 0,5-1,5

Milk sugar (lactose) - 70,0-90,0

Potato starch - 7,0-15,0

Polyvinylpyrrolidone - 1,0-3,6

Magnesium stearate - 0,4-1,0

Part of the famous solid dosage forms introduced sodium bicarbonate, which with long-term use of the drug can cause irritation of the digestive tract.

Method of producing solid dosage forms on the basis of enalapril, including the preparation of raw materials, mixing the specified Are (lactose), hydration, granulation, drying, dusting and tableting. When the hydration is carried out at the expense of 6,6-15,0% solution of polyvinylpyrrolidone in ethanol, and wet granulation carried out by spraying an alcoholic solution of polyvinylpyrrolidone above the fluidized mass.

In a known process of manufacturing tablets used volatile organic solvents, which requires the protection of personnel from harmful fumes and equipment - additional fire and protivoiznosnyh measures, and this in turn leads to an appreciation of the process and increase the cost of the tablets.

Known solid dosage form (solid pharmaceutical composition) on the basis of enalapril maleate (see Russian Federation patent 2140261, class a 61 K 9/20, a 61 K 31/40, the filing date 03.04.1997,, date of publication, 27.10.1999, the applicant: joint stock company "ICN of Leksredstva"), selected as a prototype.

Known solid dosage form (solid pharmaceutical composition contains as the active compounds of enalapril maleate and auxiliary inert substance in the following the ratio/BR> Starch - 33,0-42,0

Polyvinylpyrrolidone - 1,0-2,0

Calcium stearate or magnesium - 1,0

Method of producing solid dosage forms (pharmaceutical solid composition) on the basis of enalapril, including the preparation of raw materials, mixing the specified active compound with a filler, which is a combination of potato starch and milk sugar (lactose), hydration, granulation, drying, dusting and tableting. While hydration is an alcoholic solution of polyvinylpyrrolidone and the dusting is apadravya a mixture of starch and calcium stearate or magnesium. And is 17-60% by weight of starch included in the composition of the granules, 40-83% in the composition apadravya mixture.

Known technical solution is the prototype has a number of significant drawbacks.

Use as a moisturizer alcohol solution of polyvinylpyrrolidone leads to a significant increase in the cost of the tablets.

When this tablet with the stated composition and obtained in a known manner has a relatively low raspadaemost, solubility and storage stability.

The objective of the proposed technical solution is the elimination of casonova of enalapril maleate, which would satisfy all the requirements of the standard pharmaceutical agent.

Problem solving and advantages of the invention ensue from the subsequent detailed description of the solid pharmaceutical compositions on the basis of enalapril maleate and specific examples of its manufacture.

The problem is solved due to the fact that the solid pharmaceutical composition on the basis of enalapril maleate containing as active compound of enalapril maleate and as an auxiliary inert substances lactose, starch, polyvinylpyrrolidone, calcium stearate or magnesium, according to the invention as an auxiliary inert substances it further comprises talc in the following ratio, wt.%:

Enalapril maleate - 3,8-4,7

Lactose - 40-60

Starch - 25-55

Polyvinylpyrrolidone - 1,0-10,0

Calcium stearate or magnesium - 0,4-1,0

Talc - 1,0-3,0

In addition, the problem is solved due to the fact that in a method of producing solid pharmaceutical compositions on the basis of enalapril maleate containing as active compound of enalapril maleate and auxiliary inert substances, including the preparation actoz, the wetting solution of polyvinylpyrrolidone, granulation, drying, dusting apadravya mixture and tableting, according to the invention, the mass ratio of the filler starch : lactose is 1:1-1,5 respectively, and the moisture carried out through the combined humidifier containing 2-4% solution of starch paste and 15-20% solution of polyvinylpyrrolidone in the mass ratio of the combined humidifier to irrigated weight of 1:3-5.

To solve the problem in the method according to the invention is 0.5-1% of the mass containing solid pharmaceutical composition of starch is introduced into the starch paste, 93-95% in the composition of the filler, and 5-7% in the composition apadravya mixture comprising starch, talc, calcium stearate or magnesium.

According to the invention, a pharmaceutical solid composition made in the form of tablets.

The claimed pharmaceutical solid composition is the product of the antihypertensive effect and can be used in the treatment of hypertension and congestive heart failure.

The active compound in the inventive pharmaceutical solid composition is enalapril in the form of a salt of maleic Illowy alcohol) and has the following chemical formula: 1-[N-[(S)-1-carboxy-3-phenylpropyl]-L-alanyl]-L-Proline-1'-ethyl ester.

Properties and quality of the final tablet to a large extent depends on the ancillary of inert substances, so in addition to the active compound of the proposed solid pharmaceutical composition as an auxiliary inert substances contains lactose, starch, polyvinylpyrrolidone, magnesium stearate, talc. The composition and quantity of the inert auxiliary substances are optimal and identified experimentally.

The proposed ratio connection is active and inert auxiliary substances is also an optimal found experimentally and provided quality tablets with high therapeutic effect of the active compounds and which comply with the requirements of the State Pharmacopoeia XI strength, solubility, raspadaemosti etc.

Failure to comply with the limit of the ratio of one of the components of the composition in compliance with the proposed limits of the ratios of all other components of the composition does not allow to achieve a positive effect.

The claimed pharmaceutical solid composition structurally is compressed between the granules mostly 2-4 mm, containing nathanialstill in the claimed composition.

In addition, the granules contain matrix-based starch and polyvinylpyrrolidone formed of 2-4% solution of starch paste (0.5-1 wt. % of dry starch) and 15-20% aqueous solution of polyvinylpyrrolidone (1.0 to 10.0 wt.% dry polyvinylpyrrolidone). An active connection is in close contact with these matrices. Granules Audrey apadravya mixture comprising magnesium stearate, talc, starch, taken mainly in the amount of 5-7% by weight of the total starch present in the claimed composition.

The inventive composition includes additives that facilitate the pressing of powder materials and give the tablets strength. As such a filler in the inventive compositions use a combination of starch and lactose. Lactose is a disaccharide that is suitable for pressing, in particular from the viewpoint of flowability preferred anhydrous lactose, although you can apply water lystrosaurus lactose. The presence in the claimed composition specified in the filler quantity of starch and lactose (1:1-1,5 respectively) not only facilitates the pressing, but also can significantly increase the rate of release of active compound, while was polzovali starch, the amount of which was determined experimentally. The presence in the claimed composition specified number of starch largely determines the rate of release (the rate of acceleration of the disintegration of the tablet after swallowing to ensure rapid release of the active compound), the speed and completeness of absorption of the active compounds (bioavailability), as well as its stability. In addition, the starch provides the conditions for the penetration of liquid (water and/or digestive juices) into solid pharmaceutical composition. The reduction of starch (less than 25.0% of the weight of the tablet) leads to an increase in time raspadaemosti tablets, and the increase in starch (more 55,0% by weight of the tablet) to reduce the strength, stability and increase the abrasion of the tablets.

It is assumed that the presence of the polymer contributes to the wetting and dissolution of poorly soluble active compounds. In the claimed composition using such a polymer, such as polyvinylpyrrolidone medical low molecular weight with a molecular mass of 8000-12000, the amount of which was determined experimentally.

The choice of this polymer due to the fact that he allowed to be used in shocksite, it is soluble and is released by the industry. The inclusion in the inventive composition polyvinylpyrrolidone leads to a significant increase in the dissolution rate of the active compounds of enalapril maleate.

The main criteria for choosing the number of lactose, starch, polyvinylpyrrolidone were pharmaceutical and therapeutic usefulness.

As moving substances in the inventive compositions use an auxiliary inert substances, which reduce the friction between the particles inside the tablet, reducing the reaction forces that appear on the walls of the matrix. In the proposed composition as moving substances used starch, magnesium stearate and talc. The inclusion of these substances in the inventive composition reinforce the slide and provide a uniform filling of the space in the matrix, while receiving the tablets with a constant weight.

The presence in the inventive composition stearate provides the effect of slip required at the stage of pressing, as it is the effect of slip causes the uniformity of the mechanical and physical properties in the volume of the dosage form, thereby facilitating the formation of the smooth surface of tectura dosage forms and worsens raspadaemost, granules of the claimed composition Audrey mixture of stearate, taken in an amount of not more than 1 wt.h., starch, taken at the rate of 5-7% of the total mass containing starch, and talc, taken not more than 3 wt.h.

The presence in the claimed composition of talc provides not only the effect of the sliding, but also gives the finished tablets Shine.

In this case a reduction of the sliding substances: magnesium stearate (less than 0.4% by weight of the tablet) and talc (less than 1.0% by weight of the tablet) leads to ethnological tabletting process, i.e. to the deterioration of the sliding properties of the granulate in the tabletting process, and increasing the amount of lubricating substances: magnesium stearate (more than 1.0% by weight of the tablet) and talc (more than 3.0% by weight of the tablet) does not lead to a significant improvement of the technological characteristics of the mass for tableting, and, moreover, prohibited by the requirements of the State Pharmacopoeia XI release 2.

As can be seen from the above, only the proposed intervals of the ratios of components are optimal and can achieve a non-toxic drug in tablet form and meet the requirements of scientific and technical documentation on all counts.

Use when receiving granulate combined humidifier when the claimed value of the humidifier to irrigated weight provides good adhesion of the active compound and the inert auxiliary substances, which contributes to a significant increase in the durability of tablets and thereby reduces their rejection in the process of packing.

The number you enter in the composition of the humidifier starch is 0.5-1% of the total weight of starch, containing in the claimed composition. The rest of the starch is E. these ratios impair the technological properties of the granulate (flowability, the compressibility) and hampers the process of tableting.

Use for dusting mixture consisting of starch, magnesium stearate and talc, also provides good adhesion of the active compound and the inert auxiliary substances, which contributes to a significant increase in the durability of tablets and thereby reduces their rejection in the process of packing.

Thus, the combination of these features of the claimed composition was allowed to achieve its raspadaemosti when administered for 5-7 minutes. The solubility of the claimed composition has considerably increased and as a consequence improved bioavailability of the active compounds of enalapril maleate.

While the claimed composition has good mechanical strength is not destroyed when the load reaches 4 kg.

The inventive composition has a high chemical stability - after 2 years of storage the content of impurities was within the limits specified in the regulatory documentation, and amounted to less than 1.0%.

The claimed technical solution is different from the prototype (see the patent of the Russian Federation 2140261, class a 61 K 9/20, a 61 K 31/40, the filing date 03.04.1997,, date of publication, 27.10.1999, will argue the need to explicitly studied the prior art, it has an inventive step.

The claimed technical solution can be obtained and used in industry, therefore, meets the criterion of "industrial applicability".

Specific example

Preparation of solid pharmaceutical compositions on the basis of enalapril maleate is carried out by preparation of raw materials, preparation of the combined humidifier, mixing, wetting, wet granulation, drying of the granulate, dry granulation and dusting with subsequent pelletizing.

1. Preparation of raw materials includes the screening of enalapril, lactose, starch and drying of the starch (5-7% by weight of the tablet) used for dusting, up to 5-7% moisture content.

2. The preparation of the combined humidifier.

Prepare a 15% aqueous solution of polyvinylpyrrolidone. Prepare a 4% solution of starch paste. Complete solutions combine

3. The mixing.

On the scales weighed 43 g of enalapril maleate, 433,5 g starch 20% humidity, 500 g of lactose.

In the mixer load of enalapril maleate, starch and lactose and stirred for at least 5-10 minutes.

At the end of premesis the achievement of uniform wetting.

4. Wet granulation.

The wetted tablet mass is passed through a granulator with a grid cell size of 2 mm

The formation of granules consisting of enalapril maleate, starch, lactose and polyvinylpyrrolidone.

5. Drying granulator.

Drying granulator is produced in a vacuum drying Cabinet at a temperature of 45-50oC for 1.5 to 4 hours. When drying, an optimum particle size tablet mass.

6. Dry granulating and dusting.

On the scales weighed starch 5-7% humidity, magnesium stearate and talc.

The dried pellet mass is passed through a granulator and add to it in small portions weighed quantity of starch, magnesium stearate and talc.

The dry granules are poured into the mixer, add outrivals mixture and stirred for 5-10 minutes.

7. Tableting.

The prepared tablets weight tabletirujut on a tablet press, after adjusting the average weight of the tablets and selecting the optimal pressure. During pressing of the granules polyvinylpyrrolidone and starch to form the matrix, providing a quick raspadaemost and VTEM tablets dedust and sent for packaging.

Tablets on the basis of enalapril are white with a yellowish white color, smooth surface, face shape with beveled edges and scored.

The average weight of 230 mg tablets, 8 mm in diameter and a height of 3.6 0,4 mm

Tablets of geometric shape and size meet industrial standard (OST 67-7-170-75), appearance, strength, dissolution, raspadaemosti and other indicators meet the requirements of the State Pharmacopoeia XI.

To assess the dissolution of the tablets use the index T100%that means the time during which the active compound is completely converted into solution. Determining the values of T100%carried out according to the State Pharmacopoeia of the USSR XI, issue 2, S. 154, using the device "Torque basket". Environment dilution water.

When the volume of the dissolution of 500 ml and the speed of rotation of the basket 100 rpm, we get that the number of active connections of enalapril maleate, passed into the solution after 45 minutes, there were more than 80% of the number contained in the tablet.

The obtained experimental series of tablets were laid on accelerated and natural storage for studying the stability of the preparation and establishment period godnot the flaxes during storage and do not change their rates within 2 years.

Thus, compared with the prototype of the proposed technical solution is more stable during storage, easily releases the active compound of apalapsili maleate, which ensures its high bioavailability.

The sequence of operations and their technological options allow you to produce a solid pharmaceutical composition on the basis of enalapril maleate, the quality of which meets all the requirements of qualitative and quantitative indicators standard pharmaceutical agent.

1. Pharmaceutical solid composition on the basis of enalapril maleate containing as active compound of enalapril maleate and as an auxiliary inert substances lactose, starch, polyvinylpyrrolidone, calcium stearate or magnesium, characterized in that as an auxiliary inert substances, it further comprises talc in the following ratio, wt.%:

Enalapril maleate - 3,8 - 4,7

Lactose - 40 - 60

Starch - 25 - 55

Polyvinylpyrrolidone - 1,0 - 10,0

Calcium stearate or magnesium - 0,4 - 1,0

Talc - 1,0 - 3,0

2. A method of obtaining a solid pharmaceutical compositions on the basis of enalapril maleate containing Cauchy preparation of raw materials, the specified mixing the active compound with a filler, which is a combination of starch and lactose in their mass ratio of 1: (1-1,5), respectively, hydration combined humidifier containing 2-4% solution of starch paste and 15-20% aqueous solution of polyvinylpyrrolidone in the mass ratio of the combined humidifier to irrigated weight of 1:(3/5), respectively, granulation, drying, dusting apadravya mixture comprising starch, talc, calcium stearate or magnesium, and tableting.

3. The method according to p. 2, characterized in that 0.5 to 1% by weight is contained in the solid pharmaceutical composition of starch is introduced into the starch paste, 93-95% in the composition of the filler, and 5-7% in the composition apadravya mixture.

4. The method according to p. 2, characterized in that the solid pharmaceutical composition is made in the form of tablets.

 

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