RU2254854C2 - Analgesic, antipyretic, anti-inflammatory preparation and method for its preparing - Google Patents

Abstract

FIELD: medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to producing a medicinal preparation with analgesic, antipyretic and anti-inflammatory effect. The preparation is made as a tablet comprising a core containing ibuprofen as an active substance wherein a core is covered by envelope masking taste of the preparation. Core comprises potato starch and calcium stearate as special additives, and envelope comprises sugar, magnesium basic carbonate, polyvinylpyrrolidone, aerosil, talc, titanium dioxide, gelatin, vanillin, dye acid red and bee wax. Invention provides the necessary quality and necessary therapeutic effect of tablets due to rapid release of active substance from the tablet core wherein the core decomposition is 7-8 min and that in dissolving and 92-94% of active component transfers to medium in 45 min.

EFFECT: improved method for preparing, improved and valuable medicinal and pharmaceutical properties of preparation.

4 cl, 1 tbl, 5 ex

Description

The invention relates to the pharmaceutical industry, in particular to the production of drugs with analgesic and antipyretic effects containing ibuprofen.

It is known that ibuprofen is one of the modern non-steroidal drugs with anti-inflammatory, analgesic and antipyretic activity. Ibuprofen is used to treat rheumatoid arthritis, deforming osteoarthrosis, osteochondrosis of the spine, with some inflammatory lesions of the peripheral nervous system. But it is contraindicated in acute ulcers and exacerbations of peptic ulcer of the stomach and duodenum, ulcerative colitis, as well as in diseases of the optic nerve (see MD Mashkovsky "Medicines". A manual for doctors, t.1, p.169, ed 14th, M., 2000).

Ibuprofen is a white crystalline powder, practically insoluble in water and easily soluble in alcohol. The drug is well absorbed from the gastrointestinal tract, is relatively quickly and completely eliminated from the body, which leads to a high concentration of ibuprofen in the urine and its effectiveness in urogenital infections. Therefore, to ensure the therapeutic effect of the drug, the ibuprofen dosage form must quickly release the active ingredient.

Ibuprofen has an unpleasant taste and belongs to the category of drugs that require masking their taste.

As a prototype, a tablet-shaped preparation was selected, comprising a core containing the active substance - ibuprofen and pharmaceutical target additives, coated with a polymer coating masking the taste of ibuprofen (see patent specification No. 2085190 "Solid dosage form for oral administration of pharmaceutically active substances, having unfavorable organoleptic properties ", publ. 07/27/97, patent owner Eurand International S.p.A., Italy). The shell further comprises a pharmaceutically acceptable organic acid, for example citric or ascorbic, to reduce or prevent the dissolution of the shell in the oral cavity. However, it is possible that the presence of acid in the shell can also give an unpleasant aftertaste in the mouth.

For the manufacture of tablet cores, a technology is used that is classical in the pharmaceutical industry, including preparation of raw materials, preparation of a tablet mass by mixing ibuprofen and pharmaceutical target additives, wet granulation, drying, dry granulation, dusting, and compression of the granulate into tablet cores.

The coating is carried out by spraying a previously prepared suspension.

However, this drug and the method of its production do not provide sufficient strength.

The objective of the invention is to expand the range of domestic medicines containing ibuprofen with improved organoleptic properties, and the development of an inexpensive method that eliminates the use of expensive ingredients and allows you to get high-quality drug in the form of durable tablets that preserve the therapeutic effect over their shelf life.

The invention provides an analgesic, antipyretic, anti-inflammatory drug, made in the form of a tablet, comprising a core containing the active substance - ibuprofen and pharmaceutical target additives, coated with a mask masking the taste of ibuprofen, while the target additive contains potato starch and calcium stearate in the following the ratio of components in wt.%:

Ibuprofen 79.2-87.5, preferably 83.33;

Potato starch - 12.4-19.8, preferably 15.67;

Calcium stearate is 0.1-1.0, preferably 1.0.

A method for producing an analgesic, antipyretic, anti-inflammatory drug, made in the form of a coated tablet, comprising obtaining a core tablet containing the active substance ibuprofen, by preparing raw materials, obtaining a mass for tabletting the core, moistening it, wet granulation, drying, dry granulation , dusting, pressing the granulate into a tablet core, while the tablet mass is obtained by mixing ibuprofen and starch, moisten the mixture with a solution of 7% starch adhesive Era, dusting the obtained granules is carried out with starch and calcium stearate with a ratio of components in wt.%: ibuprofen - 79.2-87.5, potato starch - 12.4-19.8, calcium stearate - 0.1-1.0, while starch is consumed in the following amounts: to obtain mass for tabletting 74-75%, for the preparation of starch paste, 13-14%, for dusting 11-12%.

In addition, to give the tablet cores a biconvex shape, the granulate is pressed on a punch with a diameter of 10 mm and a radius of curvature of 0.75 of the diameter of the punch.

New in the proposed composition of the drug (core), in comparison with the known, is that it contains potato starch and calcium stearate as target additives with a new ratio of ingredients. The claimed ratio of ingredients found experimentally, is optimal and provides the necessary quality of tablets and therapeutic effect of the drug. Failure to comply with the limit ratio of one of the ingredients while observing the claimed limits of the ratios of all other ingredients of the product does not allow to achieve a positive effect. The use of starch in the specified proportion provides a quick release of the active substance from the tablet core. The disintegration of the nucleus is 7-8 minutes and when it is dissolved after 45 minutes, 92-94% of ibuprofen passes into the dissolution medium. A decrease in starch leads to an increase in the disintegration time of tablets, and an increase in starch leads to a decrease in tablet strength. A change in the ratio at the wetting stage worsens the wetting of the powder mixture, which increases the mixing time required for an even distribution of moisture. The use of calcium stearate as a sliding substance makes it possible to achieve flowability of the granulate, which ensures the normal tabletting process. A decrease in calcium stearate worsens the sliding properties of the granulate during tabletting, and an increase (more than 1.0 wt.%) Is prohibited by the requirements of GF X1, issue 2.

The biconvex form of the tablet core increases the convenience of applying the shells.

In addition, the invention provides an analgesic, antipyretic, anti-inflammatory drug, made in the form of a tablet, comprising a core containing the active substance - ibuprofen, coated with a mask that masks the taste of ibuprofen, while the shell contains: sugar, basic magnesium carbonate, polyvinylpyrrolidone, aerosil, talc titanium dioxide, gelatin, vanillin, acid red, beeswax in the following ratio of components in wt.%:

Sugar - 60-90, preferably 77.78;

Magnesium carbonate basic - 3-33, preferably 17.1;

Polyvinylpyrrolidone - 0.1-2.5, preferably 1.3;

Aerosil - 0.1-9.0, preferably 1.0;

Talc - 0.1-3.0, preferably 1.0;

Titanium dioxide - 0.1-1.5, preferably 0.8;

Gelatin - 0.1-1.0, preferably 0.7;

Vanillin - 0.1-2.5, preferably 0.18;

Acid red is 0.08-0.25, preferably 0.13;

Beeswax is 0.005-0.015, preferably 0.01.

A method is also proposed for producing this analgesic, antipyretic, anti-inflammatory drug in the form of a tablet, which includes producing core tablets containing the ibuprofen active ingredient and coating the coating for taste masking of ibuprofen, in which the coating is carried out in a coating pan, before coating primer of core tablets by alternating moistening them with sugar syrup containing 10% aqueous solution of polyvinylpyrrolidone and dusting with magnesium carbonate followed by exposure of the tablet cores in air for 12 hours, and the coating is applied in layers by alternating the methods of moistening the tablet cores with a suspension, which is a composition of colored sugar syrup, 10% aqueous solution of polyvinylpyrrolidone, talc, aerosil, vanillin, magnesium carbonate, and drying, then the tablets are sequentially sanded and glossed.

Before the ground, they carry out the heating of the tablet cores with filtered warm air 30-40 ° C to a temperature of 20-25 ° C.

At the primer stage, the ratio of sugar syrup to 10% aqueous solution of polyvinylpyrrolidone was taken as 5: 1.

Magnesium carbonate basic is consumed in the following amounts: for a primer of 39-40%, for the preparation of a suspension for layering a coating of 60-61%.

Drying the tablets after wetting the suspension is carried out with warm air at 35-40 ° C.

The tablets are ground by alternating techniques of moisturizing with a composition containing an aqueous solution of gelatin in colored syrup and drying.

When applying the shell, 65-68% sugar syrup is used when consumed in the following amounts: for the preparation of a 10% solution of polyvinylpyrrolidone 11-12%, for a primer 11-12%, when preparing the suspension for coating 65-66%, when grinding 11- 12%.

The tablets shine in a waxed pan, until a steady shine appears on them.

Sugar turned out to be the most acceptable as a shell base, basic magnesium carbonate as a filler, polyvinylpyrrolidone and gelatin as a plasticizer, aerosil and talc as a sliding agent, dioxide and acid red as a titanium dye.

The combined use of these ingredients in the above ratios allows you to get a shell that has the necessary strength for subsequent packaging, while ensuring the stability of the composition during storage and improves organoleptic properties. The dye introduced into the shell significantly improves the appearance by imparting a uniform pleasant color. Glossy substances enhance this effect, forming gloss on the surface of the shell. The lower limit of the content of glossy substances, like dye, is determined by the presence or absence of the corresponding effect, and the upper one is determined by economic feasibility.

In addition, the use of the specified shell along with the core of the claimed composition leads to the rapid release of the active compound from the dosage form. This ensures rapid absorption of the active substance in the gastrointestinal tract, minimizing the possibility of side effects.

The resulting pharmaceutical composition meets the requirements of GF X1 (in appearance, disintegration, dissolution, dosage uniformity and other indicators), is stable during storage and has a shelf life of more than 3 years.

Conducted patent research did not reveal similar technical solutions, which allows us to conclude about the novelty and technical level of the claimed technical solution.

The invention is illustrated by the following examples.

Ingredients Content, wt.% Examples 1 2 3 4 5 Nucleus Ibuprofen 83.33 85 82.0 87.5 79.2 Potato starch 15.67 14,4 17.6 12,4 19.8 Calcium stearate 1,0 0.6 0.4 0.1 1,0 Total: 100 100 100 100 100 Shell Sugar 77.78 68.0 61.0 90.0 80.0 Magnesium carbonate basic 17.1 3.0 33.0 3.0 6.0 Polyvinylpyrrolidone 1.3 1,0 0.5 0.1 2,5 Aerosil 1,0 7.0 0.7 0.1 9.0 Talc 1,0 3.0 2.0 0.41 0.1 Titanium dioxide 0.8 1,0 1,0 0.1 1,5 Gelatin 0.7 0.34 1,0 0.1 0.5 Vanillin 0.18 2,5 0.595 0.1 0.135 Acid Red 2C 0.13 0.15 0.2 0.08 0.25 Beeswax 0.01 0.01 0.005 0.01 0.015 Total: 100 100 100 100 100 Quality indicators  
   
   
   
  Disintegration, min 2 3 4 8 7 Dissolution,% in 45 min in phosphate buffer pH = 7.2 95 92 88 80 83  
   
   
   
 

Example 1. Obtaining ibuprofen core tablets 0.2 g. The number of loaded components is indicated to obtain 10 kg of core tablets.

Preparation of raw materials includes: screening of starch, calcium stearate, crushing of ibuprofen, preparation of a humidifier 7% starch paste solution;

Preparation of 7% starch paste: dry starch in the amount of 0.21 kg (taking into account moisture 15% - 0.247 kg) is suspended in 0.6 l of cold water. The resulting suspension is poured into 2.19 liters of boiling water. The paste is cooled to a temperature of 20-30 ° C.

Getting the mass for tabletting includes the following operations:

- mixing in the mixer 8.3 kg of ibuprofen and 1.2 kg of dry starch, mixing for 10-15 minutes;

- moistening the tablet mixture with a 7% starch paste solution by stirring for 15 minutes until the moisture is evenly distributed;

- wet granulation is carried out by wiping the wet tablet mixture through a perforated mesh granulator with a hole diameter of 5 mm;

- drying the tablet mass in a batch dryer SP-30 at a temperature of 30-40 ° C to a residual moisture of 2-3%;

- dry granulation by passing the tablet mass through a universal granulator with a hole diameter of 2 mm on the grid;

- dusting the dry tablet mixture (mass) in a batch dryer SP-30, loading starch into it - 0.19 kg (taking into account moisture 5% - 0.2 kg) and calcium stearate - 0.1 kg.

Tableting: the tablet mass is tableted on a RTM-41 tablet press with a punch diameter of 10 mm, the radius of curvature of the punch is

 0.75D. The average tablet weight is 0.24 + 5% g.

The obtained core tablets should be tested for the quantitative determination of ibuprofen, which should be 0.19-0.21 g.

The strength of the tablets in the manufacture of 3.0-5.0 kg, disintegration of 2.0-4.0 minutes

After receiving the positive results of the analysis, the tablets should be transferred to the coating stage.

The coating on the tablet core is carried out by the method of building up in a rotating pan-coating pan. The optimal load in the boiler is 30-36 kg of tablet cores. In the proposed example, the number of loaded components is indicated to obtain 10 kg of tablet cores.

Before coating, prepare: 65-68% sugar syrup, 10% solution of polyvinylpyrrolidone, a solution for the primer, a suspension for coating and a solution for grinding.

Sugar syrup preparation: 8.8 L of purified water is loaded into the syrup boiler and heated by supplying steam in a shirt to a temperature of 90-100 ° С. Pour 5.83 kg of sugar into hot water and mix until it is completely dissolved. Boil the solution for 2 hours, periodically stirring with a wooden spatula. Cool the resulting syrup to 20-25 ° C and pass for analysis,% sugar content in the syrup should be 65-68%. At a lower concentration, continue to evaporate the syrup, at a higher dilute with the calculated amount of purified water. Filter the finished syrup through a nylon cloth, article 61KS.

Preparation of a 10% solution of polyvinylpyrrolidone (PVP): 0.1 kg of medium molecular weight polyvinylpyrrolidone should be placed in 1.0 kg of sugar syrup and left to swell for 3 hours. Mix the resulting solution thoroughly until the PVP is completely dissolved and filter through a nylon fabric, article 61KS.

Preparation of primer syrup: mix 1.0 kg of sugar syrup with 0.2 kg of 10% PVP solution.

Preparation of suspension for coating: Dissolve 10 g of acid red dye 2C by boiling in 70 ml of water. Filter the solution through several layers of gauze and pour in 6.7 kg of sugar syrup. Add 62 g of titanium dioxide to the resulting colored syrup, having previously suspended it in a small amount of syrup. 1.0 kg of the obtained colored syrup should be used at the grinding stage. In the remaining colored syrup (5.7 kg), add with stirring 0.9 kg of a 10% PVP solution, 0.075 kg of talc, 0.075 kg of aerosil, 0.013 kg of vanillin and 0.78 kg of magnesium carbonate. Add magnesium carbonate in parts of 100-150 g. Mix the suspension thoroughly until a homogeneous mixture is obtained and wipe through a nylon cloth, article 38KS.

Preparation of grinding solution: mix 0.052 kg of gelatin in 0.07 l of cold water and leave to swell for 2 hours. Then, the solution is heated with stirring to 80-85 ° C to completely dissolve the gelatin. Pour the resulting solution into 1.0 kg of colored syrup.

Primer: for the primer, prepare 0.5 kg of sifted through kapron fabric, article 38KS, magnesium carbonate. Dusty tablet cores are loaded into a pan, and heated to 20-25 ° C by supplying warm (35-40 ° C) filtered air for 15-20 minutes. Then, while rotating the boiler, pour the tablets with primer syrup in an amount of 150-200 ml. After wetting the entire surface of the tablets, evenly powder them with magnesium carbonate in an amount of 70-100 g. Continue to rotate the tablets until the magnesium carbonate is completely rolled up. Repeat the moistening and dusting operation until the sugar syrup and magnesium carbonate are fully used. The average weight of 10 tablets should be 2.7 g. Unload the primed tablets on trays and leave them in the air for 12 hours to redistribute moisture.

Coating: In a clean pan-coating boiler, load tablets and, while rotating the boiler, evenly pour them with a suspension for coating in an amount of 0.2-0.25 kg at a time. After moistening the entire surface of the tablets, apply warm air (35-40 ° C) to the boiler. Pour the dried tablets again with a suspension. Repeat the operation until the entire suspension is used. After applying the last portion of the suspension, dry the tablets (do not allow the tablets to dry out). The average weight of 10 tablets should be 3.9-4.0 g.

Grinding: After applying the suspension, stopping the flow of air, evenly pour the grinder. Rotate tablets until the surface dries without air supply. Then pour over the solution again. Repeat the operation until the grout is fully used. The flow rate of the solution for one watering is 0.15-0.2 liters. The average weight of 10 tablets should be - 0.42 g.

Glossy: to apply gloss, a waxed cauldron must be prepared. To do this, melt 5.0 kg of beeswax, drain it from the sediment and apply with a paint brush on the walls of a rotating pan-coating boiler. Apply wax evenly, avoiding gaps and roughness.

Dry tablets are loaded into the waxed boiler and rotated without air for 30-40 minutes. After the appearance of stable gloss on the tablets, unload them on trays and pass them for a full analysis. After receiving positive test results, transfer the tablets to the packaging stage.

The finished tablets are pink, the average weight is 0.42 g ± 15% (0.357-0.483) and satisfy the requirements for a pharmaceutical product.

Examples 2-5 are performed similarly. The content of ingredients and quality indicators are presented below.

Composition per tablet:

CORE:

Ibuprofen (FS 42-2823-92 or import.) - 0.2 g;

Potato starch (GOST 7699-78) - 0.0376 g;

Calcium stearate (Tu 6-09-4233-76) - 0.0024 g;

The weight of the tablet without a shell is 0.24 g;

SHELL:

Sugar (GOST 22-94) - 0.14 g;

Basic magnesium carbonate (GOST 6419-78) - 0.03073 g;

Polyvinylpyrrolidone (FS 42-1194-78) - 0.00235 g;

Aerosil (GOST 14922-77) - 0.0018 g;

Talc (VFS 42-2550-95) - 0.0018 g;

Titanium dioxide (GOST 9808-84) - 0.0015 g;

Gelatin (GOST 11293-89E - 0.00126 g;

Vanillin (GOST 16599-71) - 0.0003025 g;

Acid red 2C (VFS 42-1446-84) - 0.00024 g;

Beeswax (GOST 21179-75) - 0.0000175 g;

The weight of the tablet with the shell is 0.42 g.

Ibuprofen tablets have a good appearance and are easily swallowed, able to quickly swell, dissolve and absorb in the gastrointestinal tract.

A pharmacotoxicological study of the proposed drug “Ibuprofen-AKOS” produced by OJSC “Synthesis” was carried out in the animal laboratory of the State Pharmacological Center of Pharmacology in animal experiments in comparison with the similar foreign drug “Ibuprofen” manufactured by JSC “Olainfarm” (Latvia).

In acute experiments on non-linear white mice of both sexes, the drug “Ibuprofen-AKOS” determined the average lethal dose when administered orally, which did not differ from the same indicator for a foreign-made drug. According to the accepted classification of toxicity of substances, it can be attributed to class IV “Low toxic substances” (K.K. Sidorov, 1973).

There were no differences in the picture and time of manifestation of toxic effects of both drugs.

In a subchronic experiment on white rats of both sexes, the compared drugs were tested in two doses, which are four and eight times higher than the dose equivalent to the normal dose for humans, calculated in clinical practice guidelines, calculated on the surface of the body.

When observing animals that received test drugs for 14 days, no abnormalities were found in their appearance, condition of the coat, the nature of the secretions, and behavioral reactions.

Thus, we can conclude that the acute toxicity indices of the Ibuprofen-AKOS preparation manufactured by Synthesis OJSC for white mice and rats do not differ from the similar indicators for the Ibuprofen preparation manufactured by Olainfarm JSC (Latvia). The results of a subchronic experiment in white rats showed that the administration of the ibuprofen-AKOS drug, as well as the ibuprofen comparison drug, in doses four times higher than the equivalent to the usual dosage for humans, does not have any toxic effect on the animal organism .

Claims (4)

1. An analgesic, antipyretic, anti-inflammatory drug, made in the form of a tablet, comprising a core containing the active substance - ibuprofen, coated with a mask masking the taste of the drug, characterized in that the core contains potato starch and calcium stearate as target additives, and the shell includes sugar , basic magnesium carbonate, polyvinylpyrrolidone, aerosil, talc, titanium dioxide, gelatin, vanillin, acid red, beeswax, in the following ratio, wt.%: core: Ibuprofen 79.2-87.5, preferably 83.33 Potato starch 12.4-19.8, preferably 15.67 Calcium stearate 0.1-1.0, preferably 1.0 shell: Sugar 60-90, preferably 77.78 Magnesium carbonate base 3-33, preferably 17.1 Polyvinylpyrrolidone 0.1-2.5, preferably 1.3 Aerosil 0.1-9.0, preferably 1.0 Talc 0.1-3.0, preferably 1.0 Titanium dioxide 0.1-1.5, preferably 0.8 Gelatin 0.1-1.0, preferably 0.7 Vanillin 0.1-2.5, preferably 0.18 Acid Red 0.08-0.25, preferably 0.13 Beeswax 0.005-0.015, preferably 0.01 2. A method of producing an analgesic, antipyretic, anti-inflammatory drug made in the form of a tablet according to claim 1, including the formation of tablet cores and coating for taste masking of the drug, characterized in that the coating is carried out in a coating pan, before coating the tablet core heated with warm filtered air and primed them by alternating moistening with sugar syrup containing 10% aqueous solution of polyvinylpyrrolidone, taken in a ratio of 5: 1, and dusting magnesium rbonate, followed by exposure of the tablet cores in air for 12 hours, and the coating is applied in layers by alternating the methods of moistening the tablet cores with a suspension of a composition of colored sugar syrup, a 10% aqueous solution of polyvinylpyrrolidone, talc, aerosil, vanillin , magnesium carbonate, and drying with warm air, then the tablets are ground and polished sequentially, while grinding by alternating wetting techniques with a composition containing an aqueous solution of gelatin in colored syrup e, and drying. 3. The method according to claim 2, characterized in that when applying the coating use 65-68% sugar syrup when it is consumed in the following amounts: for the preparation of a 10% aqueous solution of polyvinylpyrrolidone 11-12%, for a primer 11-12 %, when preparing the suspension for coating 65-66%, when grinding 11-12%. 4. The method according to claim 2, characterized in that the tablets are glossed in a waxed coating pan until a stable shine appears.