RU2827329C1 - Method for preparing solid form of drug tameron in form of enteric capsules - Google Patents

Abstract

FIELD: medicine; pharmaceutics.

SUBSTANCE: invention relates to pharmacology and pharmaceutical industry and concerns a method for preparing a solid dosage form of Tameron in the form of solid enteric capsules filled with granules or modified release granules containing an active pharmaceutical substance sodium aminodihydrophthalazinedione. Granules for filling have the following versions of composition. Composition 1, wt.%: sodium aminodihydrophthalazinedione: 25–35; hydroxypropyl cellulose: 1–10, or hydroxymethyl cellulose: 1–10, or hydroxypropyl methylcellulose: 1–10; colloidal silicon dioxide: 1; magnesium stearate: 1; mannitol: up to 100 or sorbitol: up to 100. Composition 2: wt.%: sodium aminodihydrophthalazinedione: 25–35; hydroxypropyl cellulose: 1–10, or hydroxymethyl cellulose: 1–10, or hydroxypropyl methylcellulose: 1–10; polyvinylpyrrolidone: 1–5; dextran: 3–25, or sodium alginate: 3–25, or chitosan: 3–25; colloidal silicon dioxide: 1%; magnesium stearate: 1%; mannitol: up to 100% or sorbitol: up to 100%. Technical result consists in preparing a solid form of a drug preparation Tameron based on sodium aminodihydrophthalazinedione in the form of solid enteric capsules, which nucleus is composed of granules or granules with modified release, which provides the possibility of using various technologies of capsule filling by means of manual, semi-automatic and automatic methods.

EFFECT: ease of use of the preparation Tameron, manufacturability, preservation of biological activity and physical properties of the preparation, storage stability, high bioavailability, safety of use and efficacy of releasing the medicinal substance of the given dosage form.

1 cl, 2 tbl, 1 ex

Description

The drug TAMERON based on the active pharmaceutical substance sodium aminodihydrophthalazinedione belongs to the group of immunomodulatory and anti-inflammatory agents [1, 2]. The active substance of the drug works by 2 main mechanisms. In particular, TAMERON exhibits the properties of an effective antioxidant - it directly interacts with free radicals in the intracellular and extracellular environment, neutralizing them and suppressing the development of oxidative stress in cells and tissues, thus quickly modulating pro- and anti-inflammatory processes, normalizing their course [3].

Another important pathway of activity - TAMERON works at the molecular-genetic level - stabilizes the transcription factor NRF2. Due to the stabilization of this factor, the transcription of the genes it controls is significantly enhanced, protecting cells from the development of oxidative processes (glutathione reductase, glutathione peroxidase, etc.) and activating detoxification and metabolism of xenobiotics [4].

By affecting such an important cellular system as the oxidation-reduction potential, TAMERON exhibits multiple effects of application and is an effective regulator of the activity of immune cells - monocytes, macrophages, neutrophils, natural killers, responsible for different types of immunity; normalizes the phagocytic activity of the monocyte-macrophage system, the bactericidal activity of neutrophils and the cytotoxic activity of NK cells; increases the body's resistance and reduces the severity of the disease caused by a viral, bacterial or fungal infection (especially those causing acute respiratory distress syndrome); normalizes the process of antibody formation; regulates the production of endogenous interferons (IFN-α, IFN-γ) by cells and cytokines TNF-a, IL-1, IL-6.

The use of the drug TAMERON is indicated as an immunomodulatory and anti-inflammatory agent in the complex therapy of immunodeficiency states in adults and adolescents from 12 years of age: gastric ulcer and duodenal ulcer; viral hepatitis; chronic recurrent diseases caused by the herpes virus; diseases caused by the human papilloma virus; infectious and inflammatory urogenital diseases (urethritis of chlamydial and trichomonas etiology, chlamydial prostatitis, acute and chronic salpingo-oophoritis, endometritis); complications of the postoperative period in women of reproductive age; postoperative purulent-septic complications and their prevention (including in cancer patients); chronic recurrent furunculosis, erysipelas; asthenic conditions, neurotic and somatoform disorders, decreased physical performance (including in athletes); mental, behavioral and post-abstinence disorders in alcohol and drug addiction; inflammatory diseases of the oral mucosa and throat, periodontal diseases. In adults and adolescents from 12 years of age in monotherapy: acute and chronic infectious and inflammatory diseases of the gastrointestinal tract, accompanied by intoxication and / or diarrhea; chronic urogenital infections, including during immunorehabilitation measures in the interrelapse period in order to maintain clinical remission.

As an immunomodulatory and anti-inflammatory agent in the complex therapy of immunodeficiency states in children over 6 years of age: purulent surgical diseases (burn lesions, recurrent furunculosis, chronic osteomyelitis, gangrenous appendicitis with omentitis, peritonitis, purulent pleurisy); frequent recurrent diseases of the respiratory tract and ENT organs of bacterial and viral etiology (frequent acute respiratory viral infections, bronchitis, pneumonia, chronic tonsillitis, chronic otitis, chronic adenoiditis) [5].

Currently, several dosage forms of preparations based on sodium amine dihydrophthalazinedione are known - in the form of sublingual tablets, rectal suppositories, powder for the preparation of a solution for intramuscular administration, lyophilisate for intramuscular administration [6, 7]. Forms of the drug in the form of enteric-coated tablets and enteric-coated capsules have also been described [8, 9].

The previously described form of the drug based on sodium aminodihydrophthalazinedione in the form of enteric-coated capsules, the use of which releases the active substance directly into the intestine, which allows for pinpoint delivery to the site of inflammation. In this case, the capsules are filled with a core, which is a powder mixture of the main substance sodium aminodihydrophthalazinedione (100 mg) and auxiliary substances in the form of mannitol, aerosil, magnesium stearate, siliconized microcrystalline cellulose, sodium croscarmellose and dibasic calcium phosphate. Thus, the use of auxiliary substances contributes to the formation of certain properties of the powder (flowability, bulk density) and allows, with a standard capsule size, to fill it with a composition containing 100 mg of the active substance [9].

Meanwhile, it is known that sodium aminodihydrophthalazinedione is a salt formed by a strong base and a weak acid and is subject to hydrolysis, while the reaction of the solution medium of this substance is strongly alkaline (pH> 9.5). Enteric-coated capsules based on gelatin successfully pass the human stomach without being destroyed, and then, entering the intestine, dissolve releasing the core. The entry of powder from the capsule into the intestinal lumen with this method of forming the capsule core can lead to irritation of the intestinal mucosa. In different parts of the human intestine, pH is from 6 to 7.4. In the small intestine, pH gradually increases from pH 6 to approximately pH 7.4 in the terminal ileum. In the cecum, pH decreases to 5.7, but gradually increases again, reaching a value of 6.7 in the rectum [10]. Thus, the rapid release of a highly alkaline substance from the capsule can significantly destabilize the acid-base reaction in the intestinal lumen.

It is also known that the pharmacokinetics of absorption of sodium aminodihydrophthalazinedione, regardless of the dosage form known to date, is characterized by rapid absorption and a half-life of about 30-40 minutes. The above reasons - the possibility of irritation of the intestinal walls, as well as rapid absorption and a fast half-life, set the task of creating a pharmaceutical composition for filling capsules not in the form of powder, but in the form of granules, which provide a more uniform release of the active substance into the intestinal lumen without causing irritation and would provide a prolonged effect of the drug.

To ensure gradual release of the active substance, it is enclosed in granules with auxiliary components such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, magnesium stearate, mannitol, sorbitol, colloidal silicon dioxide in various ways. To ensure prolonged action, hydrophilic compounds are included in the composition of granules in addition to the above substances - polyvinylpyrrolidone, dextran, alginates, chitosan. These substances swell upon contact with liquid and form hydrogels with a physically bound network of polymer molecules carrying surface charges. They hydrodynamically and electrostatically retain ions of the active substance, which leads to its slower release from the granules [11, 12].

Thus, the objective of the present invention is to obtain a solid form of the medicinal product TAMERON based on sodium aminodihydrophthalazinedione in enteric form in the form of a capsule, the core of which is granules that ensure gradual release of the active substance and allow its action to be prolonged.

The technical result of the present invention is the production of an enteric-coated form of the drug TAMERON in the form of a capsule containing granules with the active component sodium aminodihydrophthalazinedione and auxiliary components that ensure gradual release of the drug and prolongation of its action, as well as ensuring the stability of the drug, maintaining activity and pharmacological properties.

The task at hand is solved as follows. Composition No. 1 in the form of granules for filling enteric-coated capsules is obtained by pressing and grinding, containing sodium aminodihydrophthalazinedione as the active substance and auxiliary substances in the following quantities, mass %.

aminodihydrophthalazinedione sodium - 25-35

hydroxypropyl cellulose - 1-10

or hydroxymethylcellulose - 1-10

or hydroxypropyl methylcellulose -1-10

colloidal silicon dioxide - 1

magnesium stearate - 1

mannitol up to - 100

or sorbitol up to - 100

Composition No. 2 was obtained by pressing and grinding in the form of granules for filling enteric-coated capsules, containing sodium aminodihydrophthalazinedione as the active substance and auxiliary substances in the following quantities, mass %.

aminodihydrophthalazinedione sodium - 25-35

hydroxypropyl cellulose - 1-10

or hydroxymethylcellulose - 1-10

or hydroxypropyl methylcellulose - 1-10

by livinylpyrrolidone -1-5

dextran - 3-25

or sodium alginate - 3-25

or chitosan - 3-25

colloidal silicon dioxide 1%

magnesium stearate 1%

mannitol up to 100%

or sorbitol up to 100%

The stated problem is also solved by proposing a method for producing granules of the above-mentioned types of compositions.

Granules are obtained from composition No. 1 as follows. All components used to prepare the composition are weighed. All components are sieved separately, then the following components are mixed in a drunken kidney mixer: sodium aminodihydrophthalazinedione, hydroxypropyl cellulose (or hydroxymethylcellulose or hydroxypropyl methylcellulose), half of the required mass of mannitol (or sorbitol) and colloidal silicon dioxide, half of the required mass of magnesium stearate. After mixing, the remaining half of the required mass of mannitol is added to the hopper and mixing is continued. The resulting mixture is pressed using a roller press and crushed on a screen with a preliminary cell size of 1.6 mm and a cell size on the final screen of 0.8 mm. The resulting granules are mixed with magnesium stearate and stirred to create a thin film of magnesium stearate on the surface of the granules. The resulting granules have a bulk density of about 0.54 g / ml. Next, the enteric capsules are filled with granules using a capsule filling machine. Gelatin capsules of size 00 are used for filling.

Granules from composition No. 2 are obtained as follows. All components used to prepare the composition are weighed. All components are sieved separately, then the following components are mixed in a drunken kidney mixer: sodium aminodihydrophthalazinedione, hydroxypropyl cellulose (or hydroxymethylcellulose, or hydroxypropyl methylcellulose), half of the required mass of mannitol (or sorbitol), colloidal silicon dioxide, half of the required mass of magnesium stearate, polyvinylpyrrolidone and half of the required mass of dextran (or sodium alginate, or chitosan). After mixing, the remaining half of the required mass of mannitol and the remaining half of the required mass of dextran (or sodium alginate, or chitosan) are added to the hopper and mixing is continued. The resulting mixture is pressed using a roller press and crushed on a screen with a preliminary cell size of 1.6 mm and a cell size on the final screen of 0.8 mm. The resulting granules are mixed with magnesium stearate and stirred to create a thin film of magnesium stearate on the surface of the granules. The resulting granules have a bulk density of about 0.55 g / ml. Then, enteric-coated capsules are filled with granules using a capsule filling machine. Gelatin capsules of size 00 are used for filling.

The invention is further illustrated by the following example, which should not be interpreted as limiting the scope of the invention.

Example 1. Obtaining a solid enteric-coated dosage form of TAMERON with prolonged release of the active substance using hard gelatin capsules as a shell. To obtain a solid enteric-coated dosage form of TAMERON with prolonged release of the active substance, hard gelatin capsules were used as a shell, which were filled with granules of composition 1 or 2. The technology for producing granules includes weighing all the components used to prepare the composition, then mixing the components in a drunken barrel mixer. Then, the mixture is pressed using a roller press and crushed in a sieve. At the final stage, the granules are additionally mixed with magnesium stearate to create a thin film of magnesium stearate on the surface of the granules. Then, the enteric-coated capsules are filled with granules using a capsule filling machine. For filling, gelatin capsules of size 00 are used. The amounts of substances for each batch of capsules filled with the composition according to the description of the composition of composition 1 or 2 were calculated according to the target dose of the drug, as presented in Table 1.

For the capsules obtained according to Example 1, the release profiles of sodium aminodihydrophthalazinedione were determined using a paddle stirrer-type dissolution device; the stirrer rotation speed was 50 rpm. The tests were carried out in two stages: Stage 1: the capsules were dissolved in a medium containing a 0.1 M solution of hydrochloric acid. The volume of the dissolution medium was 900 ml. The test duration was 2 hours. Stage 2 was carried out in a medium containing a 0.2 M solution of disodium hydrogen phosphate with a pH of 6.8. The volume of the dissolution medium was 500 ml. During the experiment, the solution was collected for analysis in 10 ml portions at 120, 130, 140, 160, 205 and 240 min from the start of the experiment. After collecting the sample, the dissolution medium in the beaker was not replenished. When calculating the amount of sodium aminodihydrophthalazinedione transferred into the solution, the change in the volume of the dissolution medium was taken into account. The quantitative content of sodium aminodihydrophthalazinedione in the buffer solution was determined by quantitative spectrophotometry. The measurement data are presented in Table 2/

The obtained results, presented in Table 2, allow us to state that the solid dosage form of Tameron in the form of capsules is resistant to the stomach environment and is released from the dosage form into a buffer solution simulating the intestinal lumen (pH 6.8) quite slowly. Tests to determine the release profile of the active substance simulate the process of passage of the capsule through the gastrointestinal tract: the acid stage (within 120 minutes) simulates the presence of the capsule with the active substance in the stomach, while the alkaline stage simulates the presence of the capsule in the intestine. A study of the process of release of sodium aminodihydrophthalazinedione from the capsule showed that the active substance is predominantly released (more than 90%) during the first 45 minutes in the case of using composition No. 1. This result, according to the classification, indicates immediate release, since solid dosage forms from which the active substance is released within 45 minutes in an amount of at least 75% are classified as immediate-release dosage forms. It should be noted that in the case of the granule composition according to composition 1, the release is not abrupt, but gradual. When analyzing the release of sodium aminodihydrophthalazinedione from capsules with the granule composition according to composition 2, it is evident that the concentration of the active substance increases much more slowly, with a maximum release at 2 hours of incubation in an alkaline buffer, which proves the prolonged release of the active substance. Thus, the developed dosage form allows to exclude the precipitation of sodium luminol in the form of luminol in the acidic environment of the stomach, and in the alkaline environment of the intestine it provides a slower release or a more significant prolongation of the action of the drug TAMERON.

Literature

1. Tsarkov, A.N. Innovative drug "Tameron" / A.N. Tsarkov, E.A. Tsarkova // Bulletin of the Institute of Engineering Physics. - 2019. - No. 4 (54). - P. 111-115.;

2. Ermakov, A.M. On the issue of antioxidant activity of the drug "Tameron" / A.M. Ermakov, E.A. Tsarkova // Bulletin of the Institute of Engineering Physics. - 2020. - No. 3 (57). - P. 103-106.

3. Ermakov A.M. Tameron (sodium aminodihydrophthalazinedione) as a potential combination drug for the treatment of coronavirus infection COVID-19 / A.M. Ermakov, E.A. Tsarkova, O.I. Ermakova, A.I. Tsarkov // Marine Medicine. - 2020. - Vol. 6, No. 3. - P. 67-75. - DOI 10.223 28/2413-5747-2020-6-3-67-75.

4. Scofield V.L., Yan M., Kuang X., Kim S.J., Wong P.K. The drag monosodium luminol (GVT) preserves crypt-villus epithelial organization and allows survival of intestinal T cells in mice infected with the tsl retrovirus //Immunol Lett., 2009. 122(2). P. 150-158.

5.. https://www.vidal.ru/drugs/tameron

6. Patent No. 2744858 C1 Russian Federation, IPC C07D 237/32, A61K 31/502, A61K 9/19. Method for producing sodium aminodihydrophthalazinedione lyophilisate - the medicinal product "Tameron": No. 2020116296: declared 04/28/2020: published 03/16/2021 / V. S. Volsky, A. M. Ermakov, Yu. V. Krasnova [et al.]; applicant Interregional Public Institution "Institute of Engineering Physics".

7. Patent No. 2760262 C1 Russian Federation, IPC A61K 9/02, A61K 31/502, A61P 37/02. Suppositories with sodium aminodihydrophthalazinedione: No. 2020127807: declared 19.08.2020: published 23.11.2021 / A.I. Tsarkov, E.A. Tsarkova, A.V. Chistyakova; applicant Joint Stock Company "Stoletika".

8. Patent No. 2774615 C1 Russian Federation, IPC A61K 9/28, A61K 31/502, A61K 47/12. Method for producing a medicinal product: No. 2020143829: declared 12/29/2020: published 06/21/2022 / A.M. Abidov, D.A. Malchuk.

9. Patent No. 2774597 C1 Russian Federation, IPC A61K 9/48, A61K 31/502, A61K 47/02. Method for producing a medicinal product: No. 2020143828: declared 12/29/2020: published 06/21/2022 / A.M. Abidov, D.A. Malchuk.

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Claims (4)

1. A method for producing a solid form of a medicinal product in the form of an enteric capsule based on the active pharmaceutical substance sodium aminodihydrophthalazinedione, characterized in that the components of the composition are mixed, the mixture is pressed using a roller press and crushed, the resulting granules are mixed with magnesium stearate to create a thin film of magnesium stearate on the surface of the granules, followed by filling a gelatin capsule with the resulting mixture of granules, where said composition has the following composition, wt.%: aminodihydrophthalazinedione sodium 25-35 hydroxypropyl cellulose, or hydroxymethylcellulose, or hydroxypropyl methylcellulose 1-10 colloidal silicon dioxide 1 magnesium stearate 1 mannitol or sorbitol up to 100 2. A method for obtaining a solid form according to claim 1, characterized in that polyvinylpyrrolidone, as well as dextran, or alginate, or chitosan are additionally introduced into the mixture of components of the composition in the following content, wt.%: polyvinylpyrrolidone 1-5 dextran, or sodium alginate, or chitosan 3-25