RU2764032C1 - Rapidly dissolving pharmaceutical form of indomethacin and method for production thereof (variants) - Google Patents

Abstract

FIELD: pharmaceuticals.

SUBSTANCE: group of inventions relates to medicine, namely, to a rapidly dissolving pharmaceutical form of indomethacin in the form of an effervescent granulate or a tablet, including indomethacin, polyvinyl pyrrolidone (PVP) with a molecular weight of 11,000±9,000, a granulating agent, an effervescent pair - acidic and basic components, and a glidant excipient, with the following ratio of components, wt.%: indomethacin 0.40 to 3.00, PVP-11,000±9,000 0.10 to 30.00, granulating agent 0.01 to 10.00, basic component 20.00 to 75.00, acidic component 20.00 to 75.00, glidant 0.50 to 3.00; also relates to a method for producing rapidly dissolving pharmaceutical forms of indomethacin in the form of effervescent granulate or a tablet containing no components with crystallisation water, characterised by the fact that the organic solvent is divided into two parts, in one part, a mixture of indomethacin and polyvinyl pyrrolidone with a molecular weight of 11,000±9,000 is dissolved, wherein from 1 to 100 parts of the solvent is taken per 1 part of the mixture at a temperature of 95±5°C, the resulting solution is used to granulate the powder of the basic component, in the other part of the organic solvent, a 1 to 10% solution of the granulating agent is prepared at a temperature of 95±5°C, the resulting solution is used to granulate the powder of the acidic component, the resulting basic and acidic granulates are powdered with the gildant, mixed in the ratio required to achieve a pH of 6.0±0.5 when dissolving the pharmaceutical form in water, tableted or packaged into sealed packages, and also relates to a method for producing rapidly dissolving pharmaceutical forms of indomethacin in the form of an effervescent granulate containing at least one component containing crystallisation water, characterised by the fact that a mixture of indomethacin and polyvinyl pyrrolidone with a molecular weight of 11,000±9,000 is dissolved in an organic solvent, wherein from 1 to 100 parts of the solvent is taken per 1 part of the mixture at a temperature of 95±5°C, the resulting solution is used to granulate the powder of the basic component, a 1 to 10% solution of the granulating agent is prepared in water at a temperature of 95±5°C, the resulting solution is used to granulate the powder of the acidic component, the resulting basic and acidic granulates are powdered with the gildant and packaged separately into sealed packages in the ratio required to achieve a pH of 6.0±0.5 when dissolving the pharmaceutical form in water.

EFFECT: group of inventions ensures development of a composition of rapidly dissolving effervescent granules and tablets of indomethacin, characterised by increased solubility and high release of indomethacin from the PF (99±1%), providing a therapeutically effective concentration of indomethacin in a solution in less than 5 minutes (within a time interval of 2.5±0.5 min).

19 cl, 1 dwg, 3 tbl, 15 ex

Description

Technical field

SUBSTANCE: group of inventions relates to medicine, namely to pharmaceutical production and concerns the preparation of an instant dosage form (LF) of indomethacin in the form of a tablet or effervescent granulate with increased release of the active substance (DV) from LF for internal use in the form of a solution, as a non-steroidal anti-inflammatory drug (NSAIDs).

State of the art

Indomethacin is one of the most active NSAIDs. According to the chemical structure, it belongs to the derivatives of indolacetic acid (1 - (4 - chlorobenzoyl) - 5 - methoxy - 2 - methylindolyl - 3 - acetic acid).

The pharmacological action is based on non-selective inhibition of COX, which, on the one hand, causes its pronounced anti-inflammatory, analgesic and antipyretic activity, but, on the other hand, underlies such serious side effects as erosive and ulcerative lesions of the gastrointestinal tract and nephrotoxicity with long-term use. The antiplatelet effect of indomethacin is based on a decrease in the synthesis of thromboxane A2 during inhibition of COX-1 due to a reversible decrease in platelet aggregation activity.

Indomethacin LF is prescribed systemically for inflammatory and degenerative diseases of the musculoskeletal system (back pain, rheumatism, articular syndrome, traumatic inflammation of soft tissues and joints), pain syndrome (headache and toothache, myalgia, neuralgia, after injuries and surgical interventions, accompanied by inflammation). In cases where the potential benefit justifies the use, despite the risk of adverse reactions, the drug is prescribed for algomenorrhea, inflammatory processes in the pelvis, pericarditis and premature birth. As an adjuvant, it is used for infectious and inflammatory diseases of the upper respiratory tract with severe pain. Local preparations of indomethacin are used for traumatically caused inflammation of the tendons, ligaments, muscles and joints. In ophthalmology - to inhibit miosis during cataract surgery, in the inflammatory process after surgical interventions and non-infectious conjunctivitis. In dentistry - for arthritis and arthrosis of the temporomandibular joint and inflammatory diseases of oral tissues. It was found that indomethacin has a pronounced antitumor activity against a wide range of cancer cells, which attracted the interest of researchers in relation to the study, identification and clarification of the mechanisms involved in the antiproliferative and apoptotic activity of the drug.

Indomethacin is a substance that is slightly soluble in water (it dissolves in a ratio of 1:10 ⁵ with water), which has a pronounced anti-inflammatory, antipyretic, analgesic, and also some antiplatelet action. The low solubility of indomethacin in water somewhat limits its use as an active ingredient, including in the composition of instant dosage forms.

Despite this, in recent years, there have been many examples of the use of indomethacin in the scientific literature both as part of single-component and complex medicinal products, including in the production of solid (tablets and granules) dosage forms for internal use, as well as work to increase the solubility of the substance in water. One of the important conditions for the effectiveness of the treatment of inflammatory diseases is taking into account the pharmacokinetics of drugs, in particular, such a parameter as bioavailability (BA).

Solubility in water is a fundamental parameter that affects the absorption of DV when taken orally and the achievement of the desired concentration in the systemic circulation, which affects the achievement of the required pharmacological effect. Using it, it seems possible to characterize the pharmacological activity of DV to a large extent and not experimentally predict its BD.

Despite such a wide field of application of indomethacin and high efficiency, its pronounced side effects prevent its intensive use. This determines the importance and relevance of improving and developing LF with indomethacin and is confirmed by the high interest of modern researchers in this problem.

Known effervescent tablets "Difmetre" produced by "I-Pharma Trento S.p.A." (Italy), containing 0.025 g of indomethacin, 0.075 g of caffeine, 0.002 g of prochlorperazine, as excipients (BB): anhydrous citric acid (E330), sodium bicarbonate (E500), sorbitol (E420), sodium saccharin (E954), flavor lemon, polyethylene glycol glycerylcaprylocaprate, dimethicone (E900). Indications for use for Difmetre tablets are the acute treatment of migraine with and without aura (especially in patients who experience nausea and vomiting during a migraine attack), as well as the treatment of tension-type headache attacks. Method of application - inside, after dissolving 1 tablet in 200 ml of water (1 glass). In the case of "Difmetre" it should be noted the narrowly specific indications for use (only migraine) of such an NSAID as indomethacin, which has a much wider range of applications. Accordingly, between the tablets "Difmetre" and the claimed instant, effervescent LF of indomethacin, there is a significant difference in the dosing regimen and frequency of administration. In addition, the composition of "Difmetre" is not aimed at increasing the dissolution of active ingredients, therefore, "Difmetre" tablets are more rapidly dispersed. At the same time, the ratio of indomethacin: water for taking "Difmeter" (0.025: 200) is clearly not enough for the complete dissolution of DV (1: 2500). The composition of the tablets "Difmetre" and the claimed instant, effervescent LF differ significantly. The composition of "Difmetre" additionally includes other active substances that are not always indicated when choosing indomethacin (having its own spectrum of side effects) - caffeine and prochlorperazine, which have additional side effects and contraindications. Namely: prochlorperazine - anticholinergic symptoms (sedation, constipation, dry mouth) or extrapyramidal disorders. Caffeine - due to caffeine hyperstimulation, agitation, insomnia, anxiety, tremor, tachycardia, hypertension may occur. In addition, with prolonged treatment with drugs that include caffeine, addiction reactions may develop. Abrupt discontinuation of the drug may cause headache. In the case of effervescent dosage forms developed by the authors, there is only one active ingredient - indomethacin. Accordingly, side effects can only be due to indomethacin. The set of explosives used is also significantly different - in addition to the effervescent composition, Difmetre includes: sorbitol (E420), sodium saccharin (E954), lemon flavor, polyethylene glycol glyceryl caprylocaprate, dimethicone (E900). The claimed effervescent dosage forms of indomethacin include much less explosives - only polyvinylpyrrolidone (PVP) and an effervescent composition.

A known method of obtaining a powdered water-soluble effervescent composition [RU2288594, 10.12.2006]. The method involves mixing the initial powdered acidic and carbonate components, as well as explosives, medicinal and biologically active substances with further mechanical processing by shock-abrasive effects until the formation of agglomerates of crushed particles of processed components with a size of 30-300 microns. Solid water-soluble acids, or solid acid salts, or mixtures thereof are used as acidic components. As carbonate components, biocarbonates, a carbonate, or a basic carbonate of an alkali or alkaline earth metal, or mixtures thereof, are used.

The presented compositions are also not aimed at increasing the solubility of indomethacin and are rapidly dispersing effervescent mixtures. The proposed method is acceptable for powder substances that are highly soluble in water or capable of forming water-soluble salts with other components of the mixture, which excludes its use in the case of introducing powder of poorly soluble indomethacin and its powder mixtures (not capable of increasing the solubility of indomethacin in water when mixed) into the composition of instant LF. To obtain effervescent compositions by this method, it is necessary to use only solid powdered ingredients as initial components, followed by joint grinding and further formation of agglomerates. This circumstance makes it impossible to use the proposed method for the introduction of solutions of liquid components of solid dispersions of indomethacin with polymers obtained by removing the solvent, in order to increase the solubility of active substances.

The patent "Method of increasing the water solubility of poorly soluble substances" [RU2517111, 05/27/2014] describes a method for increasing water solubility by applying a coating of microparticles of a poorly soluble calcium compound, for example, calcium phosphate or calcium carbonate, by exposure to mechanical energy (mechanical alloying or hybridization) to ensure penetrating slightly soluble microparticles of a calcium compound into a particle of a slightly soluble substance used in pharmaceutical products, veterinary pharmaceutical products, cosmetics and food products. It is believed that the calcium compounds coating the microparticles provide a wetting effect to the slightly soluble substance, and when they are removed from the slightly soluble substance and dispersed, a portion of the slightly soluble substance remains attached to them and thus increases its dispersion and solubility. The method is claimed to be applicable to any oral dosage form of sparingly soluble, sparingly soluble, very sparingly soluble and substantially insoluble AI (including indomethacin). By "dissolution" the authors mean not only the state in which the active ingredient is completely dissolved in water, but also the state in which the active ingredient is evenly dispersed in the aquatic environment.

Patent [RU2242968, 27.12.2004] describes a rapidly dispersing solid LF that does not contain gelatin, obtained by removing the solvent from a mixture containing the active ingredient (including indomethacin), modified starch and a matrix-forming agent (one or more) by freeze-drying , resulting in an open porous matrix that readily dissolves upon contact with saliva. It is noted that the matrix-forming agent may also help to maintain the dispersion of any active ingredient within a solution, suspension or mixture, which is especially useful in the case of slightly water soluble AI that must be suspended rather than dissolved.

The publication of the application for the invention [RU2005137404, 10.07.2006] describes a pharmaceutical composition containing a 5HT ₁ receptor agonist or its pharmaceutically acceptable derivative in combination with NSAIDs (including indomethacin), where the agonist and NSAIDs are located in zones separated from each other, and each zone contains an active ingredient and, optionally, a carrier, which consists of one or more components - a binder, a filler, a lubricant and an effervescent couple, a swelling agent and a lubricant, a disintegrant and a wetting agent.

The prior art also known solutions aimed at increasing the solubility of indomethacin, in particular, using the method of solid dispersions (SD), and the creation of oral forms based on it with improved biopharmaceutical characteristics. In the technology for obtaining instant LF, its TD is often used instead of the DV substance.

The patent [CN107080743 (A), 08/22/2017] describes the preparation of capsules containing solid dispersions (SD) of indomethacin. TD is obtained in the following way: dissolving a water-soluble solid dispersion carrier in a solvent with stirring, adding indomethacin and stirring for 1 hour, followed by rotary evaporation. The residue is dried in an oven for 12 to 24 hours, then crushed in a mortar and sieved through a No. 80 sieve.

A technology aimed at increasing the solubility of indomethacin by the method of solid dispersions and obtaining instant tablets is described in an article by scientists from India (Sunny J.R. et al., 2012). A comparison was made of the solubility of SD obtained by melting, where polyethylene glycols (PEG) act as carriers: PEG-4000 and Gelucire 50/13 in various ratios (1:1, 1:2, 1:4, 1:7) with the substance of indomethacin . Further, to obtain instant tablets, TDs with the best solubility and active ingredient content were selected, for which each component (TD and selected explosives: mannitol, talc, magnesium stearate, sucralose, microcrystalline cellulose and Indion/Kyron/Croscarmellose) is weighed separately and sifted through a sieve No. 60, after which all components are mixed with a pestle in a glass mortar. The mixture of powders is subjected to direct compression on a tablet machine with a punch diameter of 10 mm to obtain tablets weighing 300 mg and containing 30 mg of indomethacin.

Closest to the proposed group of inventions are solid dispersions of indomethacin and polyethylene glycol-1500 (PEG) and a method for their preparation (Krasnyuk I.I. (Jr.). Effect of solid dispersions with polyethylene glycol on the solubility of indomethacin / I.I. Krasnyuk (Jr.) , T.M. Kosheleva, A.V. Belyatskaya et al. // Chemical Pharmaceutical Journal. - 2018. - V. 52. N 3. - P. 46-49), according to which the calculated amounts of indomethacin and polymer are dissolved in ethanol 95%, then the solvent is evaporated under vacuum on a water bath at a temperature of 75+-2 ° C and vigorous stirring until constant weight. A mixture of indomethacin with PEG is prepared by jointly grinding the active ingredient and the polymer in a pharmacy mortar in a ratio of 1:5 by weight.

The main disadvantage of the known solutions is the insufficient increase in the dissolution rate and solubility of indomethacin (3 times less than that of TD with PVP). In addition, the resulting form of TD is unusable, because. is a viscous sticky mass of soft consistency.

Instant effervescent dosage forms containing indomethacin as part of TD with PVP have not been found on the modern world pharmaceutical market.

The technical problem solved by the claimed invention is the creation of an easy-to-take effervescent LF indomethacin in the form of granules or tablets with increased BD and reduced side effects.

Disclosure of invention

The technical result to which the claimed invention is directed is the development of a composition of instant effervescent granules and tablets of indomethacin, characterized by increased solubility and high release of indomethacin from LF (99 ± 1%), providing a therapeutically effective concentration of indomethacin in solution. less than 5 minutes (within the time interval of 2.5±0.5 minutes). The developed dosage forms are easy to take, provide a reduction in side effects due to obtaining the most acceptable form for absorption - in the form of a solution, as well as the absence of additional auxiliary additives. In addition, the stage of obtaining the dispersion of indomethacin-PVP and the stage of granulation are combined into one technological stage of production, which greatly simplifies the process. The ability to obtain a dosage form in the form of granules also simplifies production, eliminating the technological stage of tableting.

The technical result is achieved by creating an instant dosage form of indomethacin in the form of an effervescent granulate or tablet, including indomethacin, polyvinylpyrrolidone with a molecular weight of 15000 ± 14500, a granulating agent, an effervescent couple - acidic and basic components and a sliding auxiliary substance, in the following ratio of components, wt. %:

Indomethacin 0.40-3.00 PVP-15000±14500 0.10-30.00 Granulating agent 0.01-10.00 Main component 20.00-75.00 Acid component 20.00-75.00 sliding substance 0.50-3.00.

As a granulating agent, LF may contain polyvinylpyrrolidone with a molecular weight of 15000±14500, polyethylene glycol with a molecular weight of 400-6000, water or solvents such as alcohol, propylene glycol, glycerin.

As the main component, the LF may contain carbonates or bicarbonates of an alkali or alkaline earth metal or metals, for example, sodium carbonate or sodium bicarbonate.

As an acid component, LF may contain citric acid, tartaric acid, malic acid, ascorbic acid, lactic acid, maleic acid, fumaric acid, adipic acid, succinic acid, glycolic acid, acid salt of these acids, acidic inorganic salt, glutamic acid, adipic acid. acid, glutamic acid hydrochloride, betaine hydrochloride, or a mixture thereof.

The technical result is also achieved by creating a method for obtaining these instant dosage forms of indomethacin in the form of an effervescent granulate or tablet without components with water of crystallization, according to which the organic solvent is divided into two parts, a mixture of indomethacin and polyvinylpyrrolidone with a molecular weight of 15000 ± 14500 is dissolved in one part at a ratio of the mixture and solvent 1: 1-100 at a temperature of 95 ± 5 ° C, the powder of the main component is granulated with the resulting solution, in another part of the organic solvent, a 1-10% solution of the granulating agent is prepared at a temperature of 95 ± 5 ° C, the powder is granulated with the resulting solution acid component, the obtained basic and acid granulates are powdered with a sliding substance, mixed in the ratio necessary to achieve a pH of 6.0 ± 0.5 when the dosage form is dissolved in water, tableted or packaged in sealed packages.

Ethyl alcohol 95±1%, acetone, ether or chloroform can be used as an organic solvent.

As a granulating agent, polyvinylpyrrolidone with a molecular weight of 15000±14500, polyethylene glycol with a molecular weight of 400-6000 or anhydrous solvents such as alcohol, propylene glycol, glycerin can be used.

Alkali or alkaline earth metal or metal carbonates, for example sodium carbonate, can be used as the main component.

Anhydrous components can be used as the acid component, selected from the group: citric acid, tartaric acid, malic acid, ascorbic acid, lactic acid, maleic acid, fumaric acid, adipic acid, succinic acid, glycolic acid, acid salt of these acids, acidic an inorganic salt, glutamic acid, adipic acid, glutamic acid hydrochloride, betaine hydrochloride, or a mixture thereof.

The basic and acid granules are preferably mixed in a ratio of 4:1-1:4.

As sealed packages use stickpacks, sachets or any other known form of sealed packages.

In this case, a dosage form is obtained containing from 5 to 250 mg of indomethacin per unit dose.

The technical result is also achieved by creating a method for obtaining these instant dosage forms of indomethacin in the form of an effervescent granulate containing at least one component containing water of crystallization, according to which a mixture of indomethacin and polyvinylpyrrolidone with a molecular weight of 15000 ± 14500 is dissolved in an organic solvent at a mixture ratio of and solvent 1: 1-100 at a temperature of 95 ± 5 ° C, the powder of the main component is granulated with the resulting solution, a 1-10% solution of the granulating agent is prepared in water at a temperature of 95 ± 5 ° C, the powder of the acid component is granulated with the resulting solution, obtained basic and acid the granulates are powdered with a sliding agent and separately packaged in sealed packages in the ratio necessary to achieve a pH of 6.0 ± 0.5 when the dosage form is dissolved in water.

Ethyl alcohol 95±1%, acetone, ether or chloroform can be used as an organic solvent.

As a granulating agent, polyvinylpyrrolidone with a molecular weight of 15000±14500, polyethylene glycol with a molecular weight of 400-6000, water, steam or solvents such as alcohol, propylene glycol, glycerin can be used.

As the main component, carbonates or hydrogen carbonates of an alkali or alkaline earth metal or metals, for example sodium carbonate or sodium hydrogen carbonate, can be used.

As the acid component, for example, citric acid, tartaric acid, malic acid, ascorbic acid, lactic acid, maleic acid, fumaric acid, adipic acid, succinic acid, glycolic acid, an acid salt of these acids, an acidic inorganic salt, glutamic acid, adipic acid, glutamic acid hydrochloride, betaine hydrochloride, or a mixture thereof.

Basic and acid granulates are packed separately in sealed packages, preferably in a ratio of 4:1-1:4.

In this case, a dosage form is obtained containing from 5 to 250 mg of indomethacin per unit dose.

The proposed group of inventions provides an increase in the release of active substances due to the formation of a solid dispersion of indomethacin with polyvinylpyrrolidone, which provides a better release of indomethacin due to solubilization, increasing its solubility, dissolution rate and obtaining colloidal solutions of the medicinal substance.

Brief description of the drawings

The invention is illustrated by an illustration, where figure 1 shows the dependence of the concentration of indomethacin in solution on time (release of indomethacin): A - Developed effervescent tablets and granules (25 mg); B - Tablets "Indomethacin, 25 mg, N30" (Sopharma).

Implementation of the invention

Below is a more detailed description of the claimed invention. The present invention may be subject to various changes and modifications, clear to a person skilled in the art based on reading this description. Such changes do not limit the scope of claims.

The proposed instant dosage form of indomethacin in the form of an effervescent granulate or tablet includes indomethacin, polyvinylpyrrolidone (PVP) with a molecular weight of 15,000 ± 14,500, a granulating agent, an effervescent couple - acidic and basic components and a sliding auxiliary substance, in the following ratio, wt.%:

Indomethacin 0.40-3.00 PVP-15000±14500 0.10-30.00 Granulating agent 0.01-10.00 Main component 20.00-75.00 Acid component 20.00-75.00 sliding substance 0.50-3.00.

The mass ratio of indomethacin : PVP in the composition can be from 1: 75 to 30: 1.

At the same time, as a granulating agent, LF may contain polyvinylpyrrolidone with a molecular weight of 15000±14500, polyethylene glycol with a molecular weight of 400-6000, water or solvents such as alcohol, propylene glycol, glycerin. It is preferable to use polyvinylpyrrolidone 15000±14500 as the granulating agent.

As the acid component of the effervescent pair, the following can be selected: citric acid, tartaric acid, malic acid, ascorbic acid, lactic acid, maleic acid, fumaric acid, adipic acid, succinic acid, glycolic acid, acid salt of these acids, acidic inorganic salt, glutamic acid, adipic acid, glutamic acid hydrochloride, betaine hydrochloride, or a mixture thereof, but not limited to. It is also possible to use a mixture of two or more acids.

The main component of the effervescent pair may be a carbon dioxide precursor and may be selected from carbonate-containing compounds such as carbonates; bicarbonates or carbonates of an alkali or alkaline earth metal or metals, salts of potassium bicarbonate, calcium, sodium, lithium, ammonium; sesquicarbonates; arginine carbonate; L-lysine carbonate; sodium glycine carbonate or amino acid sodium salt carbonate, alkali or alkaline earth metal or metal phosphates and hydrogen phosphates, disodium citrate, dipotassium citrate, protonated form of lysine, arginine, potassium glycinate, sodium glycinate, meglumine, but not limited to or mixtures thereof. Mixtures of one or more bases may also be used.

Additionally, preservatives, dyes, stabilizers, flavoring agents, odor and other excipients can be included in the composition of an instant effervescent composition (granules or tablet). The formulation may further comprise one or more auxiliary processing excipients selected from soluble and insoluble lubricants. Soluble lubricants may include, without limitation, PEGs such as PEG-4000, PEG-6000 and PEG-8000, polyoxyethylene, sodium or magnesium stearatylauryl sulfate, sodium benzoate, L-leucine, adipic acid, sodium stearyl fumarate, and the like. and their combinations. Insoluble lubricants may include, without limitation, magnesium or calcium stearate, stearic acid, glycerol palmitostearate, and the like. and their combinations. The amount of sliding agent depends on the desired sliding action and is well known to those of ordinary skill in the art. Flavorings may include, without limitation, synthetic flavor oils and flavors and/or natural oils, extracts from plants, leaves, flowers, fruits, and the like. and their combinations. These may include cinnamon oil, wintergreen oil, peppermint oils, clove oil, bay oil, anise oil, eucalyptus, thyme oil, juniper berry oil, nutmeg oil, Dalmatian sage oil, bitter almond oil, acacia oil, and the like. Vanilla, citrus oil including lemon oil, orange oil, grape seed oil, lime and grapefruit oil, and fruit essences including apple, pear, peach, strawberry, raspberry, cherry, plum, pineapple, apricot, etc. are also useful as flavoring agents. d. Flavors found to be particularly useful include commercially available orange, grape, cherry and chewing gum flavors and mixtures thereof. The amount of flavoring additive may depend on a number of factors, including the desired organoleptic effect. Colorants used may include, without limitation, food, pharmaceutical, and cosmetic (FD&C) colorants, such as paints, pigments, varnishes, natural colorants, and combinations of derivatives and natural colorants. Useful varnishes include paints adsorbed on aluminum hydroxide and other suitable carriers. Examples of suitable dyes include FD&C Red #3, FD&C Red #40, FD&C Blue #1, FD&C Blue #2, FD&C Yellow #5, FD&C Yellow #6, FD&C Green #3, and combinations thereof. The amount of colorant depends on the desired aesthetic properties and is well known to those of ordinary skill in the art.

In this case, PVP, explosives and components of an effervescent pair can be either crystalline hydrates (containing water) or anhydrous.

As a result of the study of the compositions of effervescent granules and tablets for storage stability, it was found that all the compositions are stable during the specified shelf life (2 years), and their technological characteristics are within the standard values.

An important parameter is the rate of DV release from LF. Increasing the solubility and rate of dissolution of DV promotes its release from LF, its passage through biological membranes - absorption, and can increase the bioavailability of DV. In this regard, for low-water-soluble active substances, it is favorable to increase their solubility. A promising method for increasing solubility is the formation of SD. SD are bi- or multi-component nano- or colloid-dispersed systems of a medicinal substance and a carrier - solid solutions with the formation of complexes with a carrier. Polymers or combinations thereof are used as carriers. The use of TD in medicine is promising in various directions, including for increasing the BD by increasing the solubility of the DI and the rate of release from the LF. This method is used for DW with poor wettability and strong crystalline structure. Obtaining molecular dispersions or disordering of crystal structures contributes to the acceleration of the dissolution of DI.

PVP-15000±14500 in the ratio of indomethacin : PVP from 1 : 75 to 30 : 1 by weight is used as a carrier polymer for the manufacture of TD in this invention.

It should be noted that instead of polyvinylpyrrolidone with a molecular weight of 15000 ± 14500, it is possible to use various polymers, copolymers, or combinations thereof, and non-polymeric substances, polyvinylpyrrolidone with different molecular weights and its derivatives, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, ethylene vinyl acetate, N-vinylpyrrolidone and its copolymers, polypropylene, polymers of acrylic and methacrylic acids and their copolymers, poly-n-butylcyanoacrylate, polyalkylcyanoacrylates, copolymers of N-(2-hydroxypropyl)methacrylamide, α-, β-, γ-cyclodextrins and their derivatives: 2-hydroxypropyl-β -cyclodextrin, dimethyl-β-cyclodextrin, β-cyclodextrin copolymer with epichlorohydrin, poly-β-hydroxybutyrate, chitosan, cellulose and its derivatives: methylcellulose, hydroxyethylcellulose, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, cellulose phosphate, monocarboxycellulose, carboxymethylcellulose, sodium carboxymethylcellulose, phthalate acetate cellulose, cellulose acetate-butyrate, to starch, alginic acid, dextrans, dextrins, polyethylene glycols and polyethylene oxides of various molecular weights, agarose, polyurethanes, polyurethane foams, copolymers of lactic acid and glycolic acid, gel sorbents (Sephadex G-150), β-glycyrrhizic acid, lectins, carbopols, trisamine, interpolyelectrolyte complexes, polyhydric alcohols and organofluorine compounds, silicon-containing elastomers, maltodextrins, lactose, fructose, inositol, trehalose, maltose, urea, sucrose, aminocaproic acid, piracetam, sorbitol, raffinose, L-arginine, alkali metal and alkaline earth metal carbonates, tweens.

For the experiments were made samples of the proposed agent, having the following compositions shown in table 1 (wt.%).

Samples in accordance with compositions 1, 2, 5, 8, 9, 11, 13, 14, 15 were made in the form of tablets, in accordance with compositions 3, 4, 6, 7, 10 12 were in the form of granules (compositions 4, 6 , 12 - separate packaging of basic and acid granulates), while the samples of effervescent granulates were light yellow granules in the case of the basic granulate and white in the case of acid granules, the tablets had a light yellow color.

The resulting LF was tested for disintegration - effervescent tablets were analyzed according to GPM.1.4.1.0015.15, effervescent granulates - according to GPM.1.4.1.0004.15 (SP XIV, volume II). Tests showed the disintegration of LF for compositions 1-7 within the time interval of 2.5 ± 0.5 minutes, for compositions 8, 9, 11 - within 1.5 ± 0.5 minutes, for compositions 10, 12 - within 4 ,5±0.5 min, to obtain a therapeutic concentration of indomethacin (from 0.5 to 25×10 ^-2 g/l).

In addition to these dosage forms with the indicated values of the components, other dosage forms were also manufactured with the quantitative content of the components in the stated ranges, which also showed the release of DI from the LF within 99 ± 1% for less than 5 minutes.

Quickly dissolving effervescent forms of indomethacin of the following compositions have optimal release parameters, reduced irritant effect on the gastric mucosa due to the dissolution of the active ingredient in the liquid volume and create the necessary therapeutic concentration when taken (table 2):

table 2

Components LF indomethacin Indomethacin 0.60 0.61 0.64 1.91 PVP-10000 0.15-1.99 0.15-2.05 0.16-2.13 0.48-6.36 granulating agent (PVP-10000) 0.01-10.00 Main component 20.00-75.00 Acid component 20.00-75.00 Glidant (sodium benzoate) 0.50-3.00

The claimed combination of components makes it possible to obtain a drug of adequate quality and ensures the completeness of the implementation of the therapeutic effect of DV.

The inventive instant effervescent composition can be made in two ways (scheme 1 and 2) depending on the presence of water of crystallization in the composition of its constituent components. As a result of these methods, a dosage form is obtained, which may contain from 5 to 250 mg of indomethacin (measured as free substance) per unit dose.

The manufacture of effervescent granulates and tablets containing anhydrous components (components not containing water of crystallization) can proceed according to scheme 1 or scheme 2. The manufacture of effervescent granulates containing at least one aqueous component (with water of crystallization), can go according to plan 2.

The method for obtaining effervescent granulates and tablets according to scheme 1 consists in separately preparing a solution of indomethacin with PVP-15000±14500 and a solution of a granulating agent. At the same time, to obtain a solution of indomethacin with PVP-15000 ± 14500 (taken in a ratio of 1:75 - 30:1), they are dissolved in an organic solvent (from 1 to 100 parts of an organic solvent are taken for 1 part of the mixture of indomethacin with PVP), for example, in 20 parts of ethyl alcohol 95 ± 1%, at a temperature of 95 ± 5 ° C, the resulting solution is not cooled. To obtain a solution of a granulating agent, 1 part of it is dissolved in 9-99 parts of an organic solvent to obtain a 1-10% solution of a granulating agent, the resulting solution is not cooled. In this case, as a granulating agent, for example, polyvinylpyrrolidone with a molecular weight of 15000±14500, polyethylene glycol with a molecular weight of 400-6000 or any other anhydrous solvent such as alcohol, propylene glycol, glycerin is used; as an organic solvent, for example, ethyl alcohol 95±1%, acetone, ether or chloroform are used. The main component is granulated with a solution of indomethacin with PVP-15000±14500. The solution of the granulating agent is used to granulate the acid component. In this case, the basic and acidic components are taken in a ratio of 1-190:1 of the total mass of indomethacin (1-190 parts of the basic or acidic component are taken for 1 part of indomethacin). The obtained basic and acid granulates are powdered with a sliding auxiliary substance, mixed in the ratio necessary to create a pH of 6.0 ± 0.5 in solution (from 4:1 to 1:4), tableted or packaged in sealed packages, for example, sachets, with obtaining a dose of effervescent tablet or effervescent granulate, respectively, containing the required amount of indomethacin. Tablets are packed in sealed cases.

Scheme 1 allows you to combine the stages of obtaining TD, mixing components, granulation, drying and dusting within one apparatus, which contributes to the organization of continuous production with high productivity and low material and financial costs. Scheme 1 is optimal for obtaining instant granules, when using which, quickly in 2-3 minutes, you can get a ready-to-use solution of 0.025 g of indomethacin in 0.2 l (glass) of water with a patient-friendly pH of 6.0 ± 0.5.

Scheme 1 (example). Stages of manufacturing effervescent granules and tablets of indomethacin with anhydrous ingredients (organic solvent - ethyl alcohol 95±1%, acetone, chloroform, ether)

Scheme 2 allows the use of both aqueous (containing water of crystallization) and anhydrous components. The method for obtaining effervescent granulates according to scheme 2 consists in separately preparing a solution of indomethacin with PVP-15000±14500 and a solution of a granulating agent. At the same time, to obtain a solution of indomethacin with PVP-15000 ± 14500, they are dissolved in an organic solvent (from 1 to 100 parts of an organic solvent are taken for 1 part of the mixture of indomethacin with PVP), for example, in 20 parts of ethyl alcohol 95 ± 1% at a temperature of 95 ± 5°C, the resulting solution is not cooled. To obtain a solution of the granulating agent, 1 part of it is dissolved in 9-99 parts of the granulating liquid - water - to obtain a 1-10% solution of the granulating agent. The main component is granulated with a solution of indomethacin with PVP-15000±14500. The solution of the granulating agent is used to granulate the acid component. The basic and acidic components are taken in a ratio of 1:1-190 of the total mass of indomethacin (1-190 parts of the basic or acidic component are taken for 1 part of indomethacin). The obtained granulates are dusted with a sliding excipient. The basic and acid granulates, without mixing, are packaged separately in sealed packages - sachets (or separate, non-communicating compartments of one sachet) in the ratio necessary to create a pH of 6.0 ± 0.5 in solution (from 4:1 to 1: 4) to obtain a dose of effervescent granulate containing the required amount of indomethacin.

In this case, for example, ethyl alcohol 95±1%, acetone, ether or chloroform are used as an organic solvent. As a granulating agent, polyvinylpyrrolidone containing water of crystallization with a molecular weight of 15000±14500, polyethylene glycol with a molecular weight of 400-6000, water, steam or solvents such as alcohol, propylene glycol, glycerin can be used .

Scheme 2 (example). Stages of manufacturing effervescent granules of indomethacin with ingredients containing water of crystallization (organic solvent - ethyl alcohol 95±1%, acetone, chloroform, ether)

Scheme 2 also allows you to combine the stages of obtaining TD, mixing components, granulation, drying and dusting within one apparatus, which contributes to the organization of continuous production with high productivity and low material and financial costs. Scheme 2 is optimal for obtaining instant granules, when using which, quickly in 2-3 minutes, you can get a ready-to-use solution of 0.025 g of indomethacin in 0.2 l (glass) of water with a pH comfortable for the patient of 6.0 ± 0.5) . Separate storage in a package (sachet) of basic and acid granulates containing crystalline water makes it possible to avoid untimely reaction of the components of the effervescent mixture before use (dissolution in water), and to ensure the proper quality of the LF throughout the entire shelf life.

Below are examples of obtaining compositions 1-15 from table 1.

Example 1

6.0 g of indomethacin, 11.9 g of PVP-10000 are dissolved in 0.12 l of ethyl alcohol 95±1% at a temperature of 95±5°C.

440.0 g of sodium carbonate powder (anhydrous), pre-crushed and sequentially sifted through sieves with a hole diameter of 250 μ and 45 μ, using a sieving machine AS 200 control (Germany) are loaded into the product container of the BOSCH “Mycrolab” granulation unit (Germany) . Fractions of particles more than 250 µm and less than 45 µm do not granulate.

Next, sodium carbonate powder is granulated with the obtained alcohol solution heated to 95±5°C, based on the calculation: 0.3±0.1 ml of granulating solution per 1 g of granulated powder.

5.3 g of PVP-10000 is dissolved in 0.10 l of ethyl alcohol 95±1% at a temperature of 95±5°C.

517.2 g of tartaric acid powder, pre-crushed and successively sifted through 250 µ and 45 µ sieves using an AS 200 control sieving machine (Germany), is loaded into the food container. Fractions of particles more than 250 µm and less than 45 µm do not granulate.

Next, the tartaric acid powder is granulated with the resulting alcohol solution heated to 95±5°C, based on the calculation: 0.2±0.1 ml of the granulating solution per 1 g of the granulated powder.

After manufacturing, a sliding auxiliary substance - sodium benzoate is introduced into the acid and basic granulates in an amount of 2% of the powdered mass, mixed in a ratio of 1.18: 1.00 (by mass). Then they are tableted at 1.01 MPa on a tablet press with a punch diameter of 2.5 cm and a finished tablet weighing 4.19 g is obtained.

The obtained tablets before use are dissolved in 0.2 l of water with a temperature of 37±5°C. The dissolution proceeds with the release of carbon dioxide (hissing). Average dissolution time 2 min 30 sec. After complete dissolution of the tablet and the end of gas evolution, a clear yellowish solution with a pH of 6.0 ± 0.5 is formed, containing 0.025 g of dissolved indomethacin, suitable for oral administration.

Example 2

6.4 g of indomethacin, 12.8 g of PVP-10000 are dissolved in 0.13 l of ethyl alcohol 95±1% at a temperature of 95±5°C.

471.0 g of sodium carbonate powder (anhydrous), pre-crushed and sequentially sieved through sieves with a hole diameter of 250 μ and 45 μ using a sieving machine AS 200 control (Germany) is loaded into the product container of the BOSCH “Mycrolab” granulation unit (Germany) . Fractions of particles more than 250 µm and less than 45 µm do not granulate.

Next, sodium carbonate powder is granulated with the obtained alcohol solution heated to 95±5°C, based on the calculation: 0.3±0.1 ml of granulating solution per 1 g of granulated powder.

4.9 g of PVP-10000 is dissolved in 0.10 l of chloroform at a temperature of 95±5°C.

485.3 g of malic acid powder, pre-crushed and sequentially sieved through sieves with a hole diameter of 250 μ and 45 μ, is loaded into the food container using an AS 200 control sieving machine (Germany). Fractions of particles more than 250 µm and less than 45 µm do not granulate.

Next, the malic acid powder is granulated with the resulting chloroform solution heated to 95±5°C, based on the calculation: 0.2±0.1 ml of the granulating solution per 1 g of the granulated powder.

After manufacturing, a sliding auxiliary substance - sodium benzoate is introduced into the acid and basic granulates in an amount of 2% of the powdered mass, mixed in a ratio of 1.03: 1.00 (by mass), then tableted at 0.73 MPa on a tablet press with a punch diameter 2.5 cm and get a finished tablet weighing 3.92 g.

The obtained tablets before use are dissolved in 0.2 l of water with a temperature of 37±5°C. The dissolution proceeds with the release of carbon dioxide (hissing). Average dissolution time 2 min 30 sec. After complete dissolution of the tablet and the end of gas evolution, a clear yellowish solution with a pH of 6.0 ± 0.5 is formed, containing 0.025 g of dissolved indomethacin, suitable for oral administration.

Example 3

6.2 g of indomethacin, 12.3 g of PVP-10000 are dissolved in 0.13 l of ethyl alcohol 95±1% at a temperature of 95±5°C.

453.3 g of sodium carbonate powder (anhydrous), pre-crushed and sequentially sifted through sieves with a hole diameter of 250 μ and 45 μ, using a sieving machine AS 200 control (Germany) are loaded into the product container of the BOSCH “Mycrolab” granulation unit (Germany) . Fractions of particles more than 250 µm and less than 45 µm do not granulate.

Next, the sodium carbonate powder is granulated with the resulting alcohol solution heated to 95±5°C, based on the calculation: 0.3±0.1 ml of the granulating solution per 1 g of the granulated powder.

5.2 g of PVP-10000 is dissolved in 0.10 l of acetone at a temperature of 95±5°C.

503.4 g of citric acid powder is loaded into the food container, previously crushed and successively sifted through sieves with a hole diameter of 250 μ and 45 μ using an AS 200 control sieving machine (Germany). Fractions of particles more than 250 µm and less than 45 µm do not granulate.

Next, citric acid powder is granulated with the resulting acetone solution heated to 95±5°C, based on the calculation: 0.2±0.1 ml of granulating solution per 1 g of granulated powder.

After manufacturing, a sliding auxiliary substance - sodium stearatylauryl sulfate is introduced into the acid and basic granulates in an amount of 2% of the powdered mass, mixed in a ratio of 1.11: 1.00 (by weight), then the mixture of granulates is packed in sealed packages - sachets.

The resulting mixture of granules granules before use is dissolved in 0.2 l of water with a temperature of 37±5°C. The dissolution proceeds with the release of carbon dioxide (hissing). Average dissolution time 2 min 30 sec. After complete dissolution of the granulate and the end of gas evolution, a clear yellowish solution with a pH of 6.0 ± 0.5 is formed, containing 0.025 g of dissolved indomethacin, suitable for oral administration.

In cases where in production, excipients containing water of crystallization are used, another option is possible.

Example 4

19.1 g of indomethacin, 38.2 g of PVP-10000 are dissolved in 0.40 l of ethyl alcohol 95±1% at a temperature of 95±5°C.

705.6 g of sodium bicarbonate powder (crystal hydrate) is loaded into the product container of the BOSCH “Mycrolab” granulation unit (Germany), pre-crushed and sequentially sifted through sieves with a hole diameter of 250 μ and 45 μ using a sieving machine AS 200 control (Germany) . Fractions of particles more than 250 µm and less than 45 µm do not granulate.

Next, sodium bicarbonate powder is granulated with the obtained alcohol solution heated to 95±5°C, based on the calculation: 0.6±0.1 ml of granulating solution per 1 g of granulated powder.

After manufacturing, a sliding auxiliary substance - PEG-6000 is introduced into the main granulate in an amount of 2% of the powdered mass.

2.3 g of PVP-10000 is dissolved in 0.10 l of water at a temperature of 95±5°C.

215.1 g of tartaric acid powder, pre-crushed and sequentially sieved through sieves with a hole diameter of 250 μ and 45 μ, is loaded into the food container using an AS 200 control sieving machine (Germany). Fractions of particles more than 250 µm and less than 45 µm do not granulate.

Next, the tartaric acid powder is granulated with the resulting aqueous solution heated to 95±5°C, based on the calculation: 0.5±0.1 ml of the granulating solution per 1 g of the granulated powder.

After manufacturing, a sliding auxiliary substance - PEG-6000 is introduced into the acid granulate in an amount of 2% of the powdered mass.

Then the acid and basic granulates in the ratio of 1.0 : 3.5 are packaged separately in sealed packages - double sachets.

The obtained granulates are mixed before use, dissolving in 0.2 l of water with a temperature of 37±5°C. The dissolution is accompanied by hissing due to the release of carbon dioxide. Average dissolution time 2 min 30 sec. After complete dissolution of the granulate and the end of gas evolution, a clear yellowish solution with a pH of 6.0 ± 0.5 is formed, containing 0.025 g of dissolved indomethacin, suitable for oral administration.

Example 5

7.0 g of indomethacin, 35.0 g of PEG-3000 are dissolved in 0.35 l of acetone at a temperature of 95±5°C.

416.0 g of sodium carbonate powder (anhydrous), pre-crushed and sequentially sifted through sieves with a hole diameter of 250 μ and 45 μ, using a sieving machine AS 200 control (Germany) are loaded into the product container of the BOSCH “Mycrolab” granulation unit (Germany) . Fractions of particles more than 250 µm and less than 45 µm do not granulate.

Next, sodium carbonate powder is granulated with the resulting acetone solution heated to 95±5°C, based on the calculation: 0.7±0.1 ml of granulating solution per 1 g of granulated powder.

5.1 g of PEG-3000 is dissolved in 0.10 l of acetone at a temperature of 95±5°C.

510.0 g of tartaric acid powder, pre-crushed and successively sifted through sieves with a hole diameter of 250 μ and 45 μ, is loaded into the food container using an AS 200 control sifting machine (Germany). Fractions of particles more than 250 µm and less than 45 µm do not granulate.

Next, the tartaric acid powder is granulated with the resulting acetone solution heated to 95±5°C, based on the calculation: 0.2±0.1 ml of the granulating solution per 1 g of the granulated powder.

After manufacturing, a sliding auxiliary substance, magnesium stearatylauryl sulfate, is introduced into the acid and basic granulates in an amount of 2% of the powdered mass, mixed in a ratio of 1.54: 1.00 (by mass). Then they are tableted at 1.01 MPa on a tablet press with a punch diameter of 2.5 cm and a finished tablet weighing 2.75 g is obtained.

The obtained tablets before use are dissolved in 0.2 l of water with a temperature of 37±5°C. The dissolution proceeds with the release of carbon dioxide (hissing). Average dissolution time 2 min 40 sec. After complete dissolution of the tablet and the end of gas evolution, a clear yellowish solution with a pH of 6.0 ± 0.5 is formed, containing 0.025 g of dissolved indomethacin, suitable for oral administration.

Example 6

20.2 g of indomethacin, 60.6 g of PVP-40000 are dissolved in 0.50 l of acetone at a temperature of 95±5°C.

682.1 g of sodium bicarbonate powder (crystal hydrate) is loaded into the product container of the BOSCH “Mycrolab” granulation plant (Germany), pre-crushed and sequentially sifted through sieves with a hole diameter of 250 μ and 45 μ using a sieving machine AS 200 control (Germany) . Fractions of particles more than 250 µm and less than 45 µm do not granulate.

Next, sodium bicarbonate powder is granulated with the resulting acetone solution heated to 95±5°C, based on the calculation: 0.6±0.1 ml of granulating solution per 1 g of granulated powder.

After manufacturing, a sliding auxiliary substance - PEG-4000 is introduced into the main granulate in an amount of 2% of the powdered mass.

3.1 g of PVP-40000 is dissolved in 0.10 l of water at a temperature of 95±5°C.

300.1 g of tartaric acid powder, pre-crushed and sequentially sieved through sieves with a hole diameter of 250 μ and 45 μ, is loaded into the food container using an AS 200 control sieving machine (Germany). Fractions of particles more than 250 µm and less than 45 µm do not granulate.

Next, the tartaric acid powder is granulated with the resulting aqueous solution heated to 95±5°C, based on the calculation: 0.3±0.1 ml of granulating solution per 1 g of granulated powder.

After manufacturing, a sliding auxiliary substance - PEG-4000 is introduced into the acid granulate in an amount of 2% of the powdered mass.

Then the acid and basic granulates in the ratio of 1.6 : 1.0 are packaged separately in sealed packages - double sachets.

The obtained granulates are mixed before use, dissolving in 0.2 l of water with a temperature of 37±5°C. The dissolution is accompanied by hissing due to the release of carbon dioxide. Average dissolution time 2 min 40 sec. After complete dissolution of the granulate and the end of gas evolution, a clear yellowish solution with a pH of 6.0 ± 0.5 is formed, containing 0.025 g of dissolved indomethacin, suitable for oral administration.

Example 7

5.7 g of indomethacin, 17.1 g of PEG-4000 are dissolved in 0.18 l of ether at a temperature of 95±5°C.

449.0 g of sodium carbonate powder (anhydrous), pre-crushed and sequentially sifted through sieves with a hole diameter of 250 μ and 45 μ, using a sieving machine AS 200 control (Germany) are loaded into the product container of the BOSCH “Mycrolab” granulation unit (Germany) . Fractions of particles more than 250 µm and less than 45 µm do not granulate.

Next, sodium carbonate powder is granulated with the resulting ether solution heated to 95±5°C, based on the calculation: 0.3±0.1 ml of granulating solution per 1 g of granulated powder.

4.8 g of PEG-4000 is dissolved in 0.10 l of chloroform at a temperature of 95±5°C.

493.0 g of citric acid powder, pre-crushed and successively sieved through sieves with a hole diameter of 250 μ and 45 μ, is loaded into the food container using an AS 200 control sieving machine (Germany). Fractions of particles more than 250 µm and less than 45 µm do not granulate.

Next, citric acid powder is granulated with the resulting chloroform solution heated to 95±5°C, based on the calculation: 0.2±0.1 ml of granulating solution per 1 g of granulated powder.

After manufacturing, a sliding auxiliary substance - L-leucine is introduced into the acid and basic granulates in an amount of 2% of the powdered mass, mixed in a ratio of 1.00: 1.10 (by weight). Then the mixture of granulates is packaged in sealed packages - sachets.

The resulting mixture of granules granules before use is dissolved in 0.2 l of water with a temperature of 37±5°C. The dissolution proceeds with the release of carbon dioxide (hissing). Average dissolution time 2 min 30 sec. After complete dissolution of the granulate and the end of gas evolution, a clear yellowish solution with a pH of 6.0 ± 0.5 is formed, containing 0.025 g of dissolved indomethacin, suitable for oral administration.

In cases where auxiliary substances containing water of crystallization are used in production, another option is possible.

Example 8

7.0 g of indomethacin, 7.0 g of PVP-2000 are dissolved in 0.11 l of chloroform at a temperature of 95±5°C.

457.8 g of sodium carbonate powder (anhydrous) is loaded into the product container of the BOSCH “Mycrolab” granulation plant (Germany), pre-crushed and successively sieved through sieves with a hole diameter of 250 μ and 45 μ using an AS 200 control sieving machine (Germany) . Fractions of particles more than 250 µm and less than 45 µm do not granulate.

Next, sodium carbonate powder is granulated with the resulting chloroform solution heated to 95±5°C, based on the calculation: 0.2±0.1 ml of granulating solution per 1 g of granulated powder.

4.7 g of PVP-2000 is dissolved in 0.10 l of chloroform at a temperature of 95±5°C.

487.3 g of citric acid powder, pre-crushed and sequentially sieved through sieves with a hole diameter of 250 μ and 45 μ, is loaded into the food container using an AS 200 control sieving machine (Germany). Fractions of particles more than 250 µm and less than 45 µm do not granulate.

Next, citric acid powder is granulated with the resulting chloroform solution heated to 95±5°C, based on the calculation: 0.2±0.1 ml of granulating solution per 1 g of granulated powder.

After manufacturing, a sliding auxiliary substance - sodium benzoate is introduced into the acid and basic granules in an amount of 2% of the powdered mass, mixed in a ratio of 1.12: 1.00 (by mass). Then they are tableted at 0.53 MPa on a tablet press with a punch diameter of 2.5 cm and a finished tablet weighing 3.64 g is obtained.

The obtained tablets before use are dissolved in 0.2 l of water with a temperature of 37±5°C. The dissolution proceeds with the release of carbon dioxide (hissing). Average dissolution time 1 min 40 sec. After complete dissolution of the tablet and the end of gas evolution, a clear yellowish solution with a pH of 6.0 ± 0.5 is formed, containing 0.025 g of dissolved indomethacin, suitable for oral administration.

Example 9

7.7 g of indomethacin, 1.1 g of PVP-20000 are dissolved in 0.39 l of acetone at a temperature of 95±5°C.

457.6 g of sodium carbonate powder (anhydrous), pre-crushed and sequentially sifted through sieves with a hole diameter of 250 μ and 45 μ, using a sieving machine AS 200 control (Germany) are loaded into the product container of the BOSCH “Mycrolab” granulation unit (Germany) . Fractions of particles more than 250 µm and less than 45 µm do not granulate.

Next, sodium carbonate powder is granulated with the resulting acetone solution heated to 95±5°C, based on the calculation: 0.9±0.1 ml of granulating solution per 1 g of granulated powder.

5.6 g of PEG-3000 is dissolved in 0.11 l of acetone at a temperature of 95±5°C.

561.0 g of tartaric acid powder, pre-crushed and successively sieved through sieves with a hole diameter of 250 μ and 45 μ, is loaded into the food container using an AS 200 control sieving machine (Germany). Fractions of particles more than 250 µm and less than 45 µm do not granulate.

Next, the tartaric acid powder is granulated with the resulting acetone solution heated to 95±5°C, based on the calculation: 0.2±0.1 ml of the granulating solution per 1 g of the granulated powder.

After manufacturing, a sliding excipient is introduced into the acid and basic granulates - magnesium stearatylauryl sulfate in an amount of 2% of the powdered mass, mixed in a ratio of 1.16: 1.00 (by mass), then tableted at 1.31 MPa on a tablet press with a punch diameter 2.5 cm and get a finished tablet weighing 3.343 g.

The obtained tablets before use are dissolved in 0.2 l of water with a temperature of 37±5°C. The dissolution proceeds with the release of carbon dioxide (hissing). Average dissolution time 1 min 30 sec. After complete dissolution of the tablet and the end of gas evolution, a clear yellowish solution with a pH of 6.0 ± 0.5 is formed, containing 0.025 g of dissolved indomethacin, suitable for oral administration.

Example 10

6.8 g of indomethacin, 464.4 g of PVP-20000 are dissolved in 4.9 l of ether at a temperature of 95±5°C.

449.0 g of sodium carbonate powder (anhydrous), pre-crushed and sequentially sifted through sieves with a hole diameter of 250 μ and 45 μ, using a sieving machine AS 200 control (Germany) are loaded into the product container of the BOSCH “Mycrolab” granulation unit (Germany) . Fractions of particles more than 250 µm and less than 45 µm do not granulate.

Next, sodium carbonate powder is granulated with the resulting ether solution heated to 95±5°C, based on the calculation: 5.3±0.1 ml of granulating solution per 1 g of granulated powder.

5.8 g of PEG-2000 is dissolved in 0.12 l of chloroform at a temperature of 95±5°C.

591.6 g of citric acid powder is loaded into the food container, previously crushed and successively sifted through sieves with a hole diameter of 250 μ and 45 μ using an AS 200 control sieving machine (Germany). Fractions of particles more than 250 µm and less than 45 µm do not granulate.

Next, citric acid powder is granulated with the resulting chloroform solution heated to 95±5°C, based on the calculation: 0.2±0.1 ml of granulating solution per 1 g of granulated powder.

After manufacturing, a sliding auxiliary substance - L-leucine is introduced into the acid and basic granulates in an amount of 2% of the powdered mass, mixed in a ratio of 1.00: 1.73 (by weight). Then the mixture of granulates is packaged in sealed packages - sachets.

The resulting mixture of granules before use, the granules are dissolved in 0.2 l of water at a temperature of 37±5°C. The dissolution proceeds with the release of carbon dioxide (hissing). Average dissolution time 4 min 55 sec. After complete dissolution of the granulate and the end of gas evolution, a clear yellowish solution with a pH of 6.0 ± 0.5 is formed, containing 0.025 g of dissolved indomethacin, suitable for oral administration.

In cases where auxiliary substances containing water of crystallization are used in production, another option is possible.

Example 11

6.3 g of indomethacin, 6.3 g of PVP-15000 are dissolved in 0.10 l of chloroform at a temperature of 95±5°C.

412.0 g of sodium carbonate powder (anhydrous), pre-crushed and sequentially sifted through sieves with a hole diameter of 250 μ and 45 μ, using a sieving machine AS 200 control (Germany) are loaded into the product container of the BOSCH “Mycrolab” granulation unit (Germany) . Fractions of particles more than 250 µm and less than 45 µm do not granulate.

Next, sodium carbonate powder is granulated with the resulting chloroform solution heated to 95±5°C, based on the calculation: 0.2±0.1 ml of granulating solution per 1 g of granulated powder.

0.1 g of PEG-1000 is dissolved in 0.005 l of chloroform at a temperature of 95±5°C.

438.3 g of citric acid powder, pre-crushed and sequentially sieved through sieves with a hole diameter of 250 μ and 45 μ, is loaded into the food container using an AS 200 control sieving machine (Germany). Fractions of particles more than 250 µm and less than 45 µm do not granulate.

Next, citric acid powder is granulated with the resulting chloroform solution heated to 95±5°C, based on the calculation: 0.2±0.1 ml of granulating solution per 1 g of granulated powder.

After manufacturing, a sliding auxiliary substance - sodium benzoate is introduced into the acid and basic granulates in an amount of 2% of the powdered mass, mixed in a ratio of 1.08: 1.00 (by mass). Then they are tableted at 1.00 MPa on a tablet press with a punch diameter of 2.5 cm and a finished tablet weighing 3.57 g is obtained.

The obtained tablets before use are dissolved in 0.2 l of water with a temperature of 37±5°C. The dissolution proceeds with the release of carbon dioxide (hissing). Average dissolution time 1 min 30 sec. After complete dissolution of the tablet and the end of gas evolution, a clear yellowish solution with a pH of 6.0 ± 0.5 is formed, containing 0.025 g of dissolved indomethacin, suitable for oral administration.

Example 12

15.3 g of indomethacin, 30.6 g of PVP-15000 are dissolved in 0.32 l of ethyl alcohol 95±1% at a temperature of 95±5°C.

564.5 g of sodium bicarbonate powder (crystal hydrate) is loaded into the product container of the BOSCH “Mycrolab” granulation plant (Germany), pre-crushed and sequentially sieved through sieves with a hole diameter of 250 μ and 45 μ using a sieving machine AS 200 control (Germany) . Fractions of particles more than 250 µm and less than 45 µm do not granulate.

Next, sodium bicarbonate powder is granulated with the resulting alcohol solution heated to 95±5°C, based on the calculation: 5.7±0.1 ml of granulating solution per 1 g of granulated powder.

After manufacturing, a sliding auxiliary substance - PEG-8000 is introduced into the main granulate in an amount of 2% of the powdered mass.

88.9 g of PEG-4000 is dissolved in 1.5 l of water at a temperature of 95±5°C.

172.1 g of tartaric acid powder is loaded into the food container, previously crushed and successively sifted through sieves with a hole diameter of 250 μ and 45 μ using an AS 200 control sifting machine (Germany). Fractions of particles more than 250 µm and less than 45 µm do not granulate.

Next, the tartaric acid powder is granulated with the resulting aqueous solution heated to 95±5°C, based on the calculation: 0.5±0.1 ml of the granulating solution per 1 g of the granulated powder.

After manufacturing, a sliding auxiliary substance - PEG-8000 is introduced into the acid granulate in an amount of 2% of the powdered mass.

Then the acid and basic granulates in the ratio of 1.00 : 2.34 are packaged separately in sealed packages - double sachets.

The obtained granulates are mixed before use, dissolving in 0.2 l of water with a temperature of 37±5°C. The dissolution is accompanied by hissing due to the release of carbon dioxide. Average dissolution time 4 min 30 sec. After complete dissolution of the granulate and the end of gas evolution, a clear yellowish solution with a pH of 6.0 ± 0.5 is formed, containing 0.025 g of dissolved indomethacin, suitable for oral administration.

Also, compositions were made with a quantitative content of components outside the stated ranges (examples 13-15), showing that the technical result is not achieved.

Example 13

5.8 g of indomethacin, 0.15 g of PVP-10000 (the polymer is taken in an amount less than allowed) is dissolved in 0.12 l of ether at a temperature of 95±5°C.

452.0 g of sodium carbonate powder (anhydrous) is loaded into the product container of the BOSCH “Mycrolab” granulation unit (Germany), pre-crushed and sequentially sifted through sieves with a hole diameter of 250 μ and 45 μ using an AS 200 control sifting machine (Germany) . Fractions of particles more than 250 µm and less than 45 µm do not granulate.

Next, sodium carbonate powder is granulated with the resulting ether solution heated to 95±5°C, based on the calculation: 0.3±0.1 ml of granulating solution per 1 g of granulated powder.

5.2 g of PVP-10000 is dissolved in 0.10 l of ethyl alcohol 95±1% at a temperature of 95±5°C.

519.7 g of tartaric acid powder, pre-crushed and sequentially sieved through sieves with a hole diameter of 250 μ and 45 μ, is loaded into the food container using an AS 200 control sieving machine (Germany). Fractions of particles more than 250 µm and less than 45 µm do not granulate.

Next, the tartaric acid powder is granulated with the resulting alcohol solution heated to 95 ± 5 ° C, based on the calculation: 0.2 ± 0.1 ml of the granulating solution per 1 g of the granulated powder.

After manufacturing, a sliding auxiliary substance - magnesium stearate is introduced into the acid and basic granulates in an amount of 2% of the powdered mass, mixed in a ratio of 1.18: 1.00 (by mass). Then they are tableted at 1.01 MPa on a tablet press with a punch diameter of 2.5 cm and a finished tablet weighing 4.19 g is obtained.

The obtained tablets before use are dissolved in 0.2 l of water with a temperature of 37±5°C. The dissolution proceeds with the release of carbon dioxide (hissing). Average dissolution time 2 min 30 sec. After complete dissolution of the tablet and the end of gas evolution, a cloudy yellowish suspension with a pH of 6.0 ± 0.5 is formed, containing less than 0.025 g (declared dose of AI) of indomethacin in dissolved form (insufficient percentage of AI release), and unsuitable for oral administration. .

Example 14

6.3 g of indomethacin, 31.5 g of PEG-3000 are dissolved in 0.26 l of ethyl alcohol 95±1% at a temperature of 95±5°C.

452.4 g of sodium carbonate powder (anhydrous) is loaded into the product container of the BOSCH “Mycrolab” granulation plant (Germany), pre-crushed and successively sifted through sieves with a hole diameter of 250 μ and 45 μ using an AS 200 control sifting machine (Germany) . Fractions of particles more than 250 µm and less than 45 µm do not granulate.

Next, sodium carbonate powder is granulated with the resulting alcohol solution heated to 95±5°C, based on the calculation: 0.5±0.1 ml of granulating solution per 1 g of granulated powder.

4.7 g of PEG-3000 is dissolved in 0.10 l of acetone at a temperature of 95±5°C.

475.2 g of malic acid powder, pre-crushed and sequentially sieved through sieves with a hole diameter of 250 μ and 45 μ, is loaded into the food container using an AS 200 control sieving machine (Germany). Fractions of particles more than 250 µm and less than 45 µm do not granulate.

Next, the malic acid powder is granulated with the resulting aqueous solution heated to 95±5°C, based on the calculation: 0.2±0.1 ml of the granulating solution per 1 g of the granulated powder.

After manufacturing, a sliding auxiliary substance, calcium stearate, is introduced into the acid and basic granulates in an amount of 2% of the powdered mass, mixed in a ratio of 4.50: 1.00 (by weight) (the acid component is taken in an amount greater than the allowable one). Then they are tableted at 0.75 MPa on a tablet press with a punch diameter of 2.5 cm and a finished tablet weighing 9.09 g is obtained.

The obtained tablets before use are dissolved in 0.2 l of water with a temperature of 37±5°C. The dissolution proceeds with the release of carbon dioxide (hissing). Average dissolution time 5 min 30 sec (more than 5 min). After complete dissolution of the tablet and the end of gas evolution, a cloudy yellowish suspension is formed with pH 2.4 ± 0.5 (less than optimal for oral administration pH 6.0 ± 0.5), containing less than 0.025 g (declared dose of AD ) indomethacin in dissolved form (insufficient percentage of release of active ingredient), and unsuitable for ingestion.

Example 15

19.1 g of indomethacin, 38.2 g of PVP-10000 are dissolved in 0.40 l of ether at a temperature of 95±5°C.

705.6 g of sodium bicarbonate powder (crystal hydrate) is loaded into the product container of the BOSCH “Mycrolab” granulation unit (Germany), pre-crushed and sequentially sifted through sieves with a hole diameter of 250 μ and 45 μ using a sieving machine AS 200 control (Germany) . Fractions of particles more than 250 µm and less than 45 µm do not granulate.

Next, sodium bicarbonate powder is granulated with the resulting ether solution heated to 95±5°C, based on the calculation: 0.6±0.1 ml of granulating solution per 1 g of granulated powder.

2.3 g of PVP-10000 is dissolved in 0.10 l of acetone at a temperature of 95±5°C.

215.1 g of tartaric acid powder, pre-crushed and sequentially sieved through sieves with a hole diameter of 250 μ and 45 μ, is loaded into the food container using an AS 200 control sieving machine (Germany). Fractions of particles more than 250 µm and less than 45 µm do not granulate.

Next, the tartaric acid powder is granulated with the resulting acetone solution heated to 95±5°C, based on the calculation: 0.5±0.1 ml of the granulating solution per 1 g of the granulated powder.

After manufacturing, a sliding auxiliary substance - sodium benzoate is introduced into the acid and basic granulates in an amount of 2% of the powdered mass, mixed in a ratio of 1.0: 3.5 (by mass). Then they are tableted at 0.67 MPa on a tablet press with a punch diameter of 2.5 cm and a finished tablet weighing 1.29 g is obtained.

The resulting tablets do not withstand storage for 2 years. The water of crystallization contained in sodium bicarbonate contributes to a premature neutralization reaction between the basic and acidic components of the effervescent system. As a result, the tablets change their appearance, break down and become substandard. When such tablets are placed in 0.2 l of water with a temperature of 37 ± 5 ° C, carbon dioxide emission (hissing) is not observed. The average dissolution time exceeds 5 minutes. A clear yellowish solution is not formed. The pH of the resulting suspension differs from the optimal 6.0±0.5. The content of dissolved indomethacin is less than 0.025 g. The solution for ingestion is unsuitable.

Table 3. The negative impact of the content of the ingredients of the developed effervescent dosage forms in an amount that goes beyond the boundary values of the intervals on the achievement of the claimed result.

Ingredient Content (wt%) When the content is less than the minimum limit value of the interval When the content is greater than the maximum limit value of the interval Indomethacin 0.40-3.00 Decreased dosage of AD less than optimal
0.025 g Increasing the dosage of AD more than optimal 0.025 g PVP-15000±14500 0.10-30.00 Increasing the value of the pressing pressure in excess of the optimum.
Reducing the strength of the tablets below the optimum.
Decreased DV release Increase in LF mass. Increasing the strength of tablets beyond the optimum.
Increasing the dissolution time of LF more than 5 minutes.
Decreased DV release Granulating agent 0.01-10.00 Increasing the value of the pressing pressure in excess of the optimum.
Decreased strength of tablets below optimal Increase in LF mass. Increasing the strength of tablets beyond the optimum.
Increasing the dissolution time of LF more than 5 minutes.
Decreased DV release Main component 20.00-75.00 Increasing the dissolution time of LF more than 5 minutes.
The decrease in the pH of the solution obtained from LF is less than the optimal 6.0 ± 0.5 Increase in LF mass. Increasing the dissolution time of LF more than 5 minutes.
Increasing the pH of the solution obtained from LF more than the optimal 6.0 ± 0.5 Acid component 20.00-75.00 Increasing the dissolution time of LF more than 5 minutes.
Increasing the pH of the solution obtained from LF more than the optimal 6.0 ± 0.5 Increase in LF mass. Increasing the dissolution time of LF more than 5 minutes.
The decrease in the pH of the solution obtained from LF is less than the optimal 6.0 ± 0.5 sliding substance 0.50-3.00 Deterioration of technological properties of granulates - flowability and angle of repose. Difficulty in ejecting the tablet from the punch and dosing the granules into packages.
Deviation of the pH of the solution obtained from LF from the optimal 6.0±0.5 Increase in LF mass.
The deterioration of the technological properties of the obtained tablets - strength.
Increasing the dissolution time of LF more than 5 minutes.
Decreased release of DV.
Deviation of the pH of the solution obtained from LF from the optimal 6.0±0.5

The ability of a medicinal product to maintain chemical, physical, microbiological and biopharmaceutical properties within certain limits throughout the shelf life is an indicator of stability. For 2 years, the stability of the claimed formulations during storage was monitored by determining quality indicators at control points: appearance, quantitative content of components, pH of an aqueous solution, dissolution time of LF, release of active ingredients from LF. All tested samples are stable systems that meet all quality requirements throughout the entire shelf life.

Thus, the result of the invention are various variants of the compositions of effervescent granules and tablets of indomethacin with a dosage of 0.025 g, which are stable systems showing disintegration within a time interval of 2.5 ± 0.5 min, obtaining in solution the required concentration of indomethacin 0.025 g per 0, 2 liters of water (one glass) and optimal processing characteristics for ease of use and storage.

The proposed methods for obtaining instant (effervescent) dosage forms of indomethacin make it possible to increase its solubility and obtain an instant dosage form convenient for taking. An increase in the release of indomethacin occurs due to the formation of a solid dispersion with PVP, which provides a better release of indomethacin from granules and tablets due to its solubilization, increasing solubility, dissolution rate and obtaining colloidal solutions.

In the case of conventional, industrial tablets available on the pharmaceutical market (Indomethacin, tab., 25 mg N30 (Sopharma)) - the release of the active substance (in 0.2 l of water at 37 ° C) occurs slowly, not exceeding a concentration of 1 after an hour 0×10 ^-2 g/l, which is consistent with the low solubility of indomethacin. The effervescent compositions developed in accordance with the invention, under the same conditions, quickly and completely release indomethacin, saturating the solution to a therapeutic concentration of 12.5×10 ^-2 g/l, in less than 5 minutes, forming a clear solution ready for use (Fig. . 1), with a pronounced anti-inflammatory, antipyretic and analgesic effect.

Claims (26)

1. Instant dosage form of indomethacin in the form of an effervescent granulate or tablet, including indomethacin, polyvinylpyrrolidone (PVP) with a molecular weight of 11000 ± 9000, a granulating agent, an effervescent couple - acidic and basic components and a sliding auxiliary substance, in the following ratio of components, wt.% : Indomethacin 0.40-3.00 PVP-11000±9000 0.10-30.00 Granulating agent 0.01-10.00 Main component 20.00-75.00 Acid component 20.00-75.00 Gliding agent 0.50-3.00. 2. The instant dosage form of indomethacin according to claim 1, characterized in that it contains polyvinylpyrrolidone with a molecular weight of 11000±9000, polyethylene glycol with a molecular weight of 400-6000, water or solvents such as alcohol, propylene glycol, glycerin as a granulating agent. 3. The instant dosage form of indomethacin according to claim 1, characterized in that it contains carbonates or hydrogen carbonates of an alkali or alkaline earth metal or metals, for example sodium carbonate or sodium hydrogen carbonate, as the main component. 4. The instant dosage form of indomethacin according to claim 1, characterized in that it contains citric acid, tartaric acid, malic acid, ascorbic acid, lactic acid, maleic acid, fumaric acid, adipic acid, succinic acid, glycolic acid as an acidic component, an acid salt of these acids, an acidic inorganic salt, glutamic acid, adipic acid, glutamic acid hydrochloride, betaine hydrochloride, or a mixture thereof. 5. A method for producing instant dosage forms of indomethacin according to claim 1 in the form of an effervescent granulate or tablet without components with water of crystallization, characterized in that the organic solvent is divided into two parts, a mixture of indomethacin and polyvinylpyrrolidone with a molecular weight of 11000 ± 9000 is dissolved in one part , at the same time, from 1 to 100 parts of the solvent are taken for 1 part of the mixture at a temperature of 95 ± 5 ° C, the powder of the main component is granulated with the resulting solution, a 1-10% solution of the granulating agent is prepared in another part of the organic solvent at a temperature of 95 ± 5 ° C, the acid component powder is granulated with the resulting solution, the resulting basic and acid granulates are dusted with a sliding agent, mixed in the ratio necessary to achieve pH 6.0 ± 0.5 when the dosage form is dissolved in water, tableted or packaged in sealed packages. 6. The method according to claim 5, characterized in that ethyl alcohol 95±1%, acetone, ether or chloroform is used as an organic solvent. 7. The method according to claim 5, characterized in that as a granulating agent use polyvinylpyrrolidone with a molecular weight of 11000±9000, polyethylene glycol with a molecular weight of 400-6000 or anhydrous solvents such as alcohol, propylene glycol, glycerin. 8. The method according to claim 5, characterized in that carbonates of an alkali or alkaline earth metal or metals, for example sodium carbonate, are used as the main component. 9. The method according to claim 5, characterized in that anhydrous components are used as the acid component, selected from the group: citric acid, tartaric acid, malic acid, ascorbic acid, lactic acid, maleic acid, fumaric acid, adipic acid, succinic acid , glycolic acid, an acid salt of these acids, an acidic inorganic salt, glutamic acid, adipic acid, glutamic acid hydrochloride, betaine hydrochloride, or a mixture thereof. 10. The method according to claim 5, characterized in that the basic and acid granulates are mixed in a ratio of 4:1-1:4. 11. The method according to claim 5, characterized in that stickpacks, sachets or any other known forms of sealed packages are used as sealed packages. 12. The method according to claim 5, characterized in that a dosage form is obtained containing from 5 to 250 mg of indomethacin per unit dose. 13. A method for producing instant dosage forms of indomethacin according to claim 1 in the form of an effervescent granulate containing at least one component containing water of crystallization, characterized in that a mixture of indomethacin and polyvinylpyrrolidone with a molecular weight of 11000 ± 9000 is dissolved in an organic solvent, while 1 part of the mixture is taken from 1 to 100 parts of the solvent at a temperature of 95 ± 5 ° C, the powder of the main component is granulated with the resulting solution, a 1-10% solution of the granulating agent is prepared in water at a temperature of 95 ± 5 ° C, the powder of the acid component is granulated with the resulting solution, the obtained basic and acid granulates are powdered with a sliding agent and packed separately in sealed packages in the ratio necessary to achieve a pH of 6.0±0.5 when the dosage form is dissolved in water. 14. The method according to claim 13, characterized in that ethyl alcohol 95±1%, acetone, ether or chloroform is used as an organic solvent. 15. The method according to claim 13, characterized in that polyvinylpyrrolidone with a molecular weight of 11000±9000, polyethylene glycol with a molecular weight of 400-6000, water, steam or solvents such as alcohol, propylene glycol, glycerin are used as a granulating agent. 16. The method according to claim 13, characterized in that carbonates or hydrogen carbonates of an alkali or alkaline earth metal or metals, for example sodium carbonate or sodium hydrogen carbonate, are used as the main component. 17. The method according to claim 13, characterized in that citric acid, tartaric acid, malic acid, ascorbic acid, lactic acid, maleic acid, fumaric acid, adipic acid, succinic acid, glycolic acid, acid salt of these acids, an acidic inorganic salt, glutamic acid, adipic acid, glutamic acid hydrochloride, betaine hydrochloride, or a mixture thereof. 18. The method according to claim 13, characterized in that the basic and acid granulates are separately packaged in sealed packages in a ratio of 4:1-1:4. 19. The method according to p. 13, characterized in that a dosage form is obtained containing from 5 to 250 mg of indomethacin per unit dose.

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