RU2732291C1 - Medicinal agent based on althaea officinalis herb for treating colds and acute respiratory diseases - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: invention refers to pharmaceutical industry, namely to a drug preparation based on Althaea officinalis herb for treating colds and acute respiratory diseases. Drug preparation based on the Althaea officinalis herb for the treatment of colds and acute respiratory diseases in the form of tablets contains a dry extract of an Althaea officinalis herb, calcium phosphate 2-substituted anhydrous, tartaric acid, calcium stearate, crospovidone and a source of terpenoids C₁₀ taken in certain amounts.

EFFECT: preparation described above provides high rate of tablets disintegration in water with simultaneous and uniform release of extractive substances.

3 cl, 19 ex

Description

The invention relates to the pharmaceutical industry, namely the production of finished dosage forms, in particular, herbal medicines for cough in the form of tablets.

The relevance of drugs based on natural components, especially of plant origin, remains high, despite the modern advances in pharmaceutical chemistry and biosynthesis. The therapeutic effect of medicinal preparations from herbal raw materials manifests itself gradually, in contrast to synthesized preparations. However, preparations of natural origin, containing a complex of biologically active substances, in contrast to synthetic ones, do not often cause allergies, are low-toxic, have a beneficial effect on the body, and with prolonged use, side effects are much less likely to appear. Herbal preparations are traditionally preferred in the group of expectorants. In addition, phytopreparations, in addition to an expectorant, have an anti-inflammatory, softening, enveloping effect. The most promising plants for the development of new dosage forms used in the treatment of colds accompanied by cough are marshmallow medicinal, licorice naked and thermopsis lanceolate (Lozhkin Y. G. "Development of the composition and technology of complex antitussive drugs of natural origin." degree of candidate of pharmaceutical sciences, Pyatigorsk, 2015).

A well-known drug based on the herb marshmallow for the treatment of colds and acute respiratory diseases "Mukaltin", which is mass-produced by the pharmaceutical industry of the Russian Federation. As a rule, the composition of the drug includes an extract of the herb marshmallow, tartaric acid, sodium bicarbonate, calcium stearate (https://medside.ru/mukaltin). Some manufacturers include, in addition to these ingredients, povidone (https://health.mail.ru/drug/mucaltin/). According to the instructions for use, the tablets are taken orally before meals or the tablet is dissolved in 1/3 cup of warm water before taking (https://medi.ru/instrukciya/mukaltin_ _{_} 308 /).

However, these drugs are not effective enough due to prolonged and uneven release of biologically active substances of the dry extract of the medicinal plant from the tablet upon dissolution. It is known that the therapeutic effect of plant extracts is due not to one active substance, but to the whole complex of biologically active substances contained in the original plant raw materials, providing a synergistic effect of the therapeutic effect of all components (Wagner H., Ulrich-Merzenich G. "Research of synergy: creating a new generation phytopreparations. "RMJ" Medical Review ", No. 3, 2016, pp. 183-189). Therefore, the effectiveness of the phytopreparation is maximum when the most complete reverse transformation of the dry extract to its original state occurs. The extract of the herb marshmallow consists of a wide range of biologically active substances: amino acids, free sugars and polysaccharides, organic acids and tannins. They have different characteristics of solubility, biological and chemical activity (Golubeva IS "Research on the standardization of raw materials and preparations of marshmallow." Abstract of the thesis for the degree of candidate of pharmaceutical sciences. Moscow, 2009). It was found that the dissolution time of the dry extract is very long. At a temperature of 20 ° C dry extract of marshmallow herb is insoluble or poorly soluble. An increase in the water temperature from 40 to 60 ° C does not lead to an improvement in solubility either in the phase ratio or in time. The optimal conditions for dissolution turned out to be the ratio of the extract to water 1: 5 and the dissolution time not less than 20 minutes at a temperature of 40 ° C (Lozhkin Yu.G. "Development of the composition and technology of complex antitussive drugs of natural origin." Abstract of the dissertation for the degree of candidate of pharmaceutical Sci. Pyatigorsk, 2015). Therefore, manufacturers of medicinal products based on plant raw materials in the form of tablets introduce into their composition various disintegrants (gas-forming mixtures, solubilizers, complexing agents, etc.) in order to ensure the rapid disintegration of tablets in a liquid medium in order to accelerate the process of dissolving the extract by dispersing solids and increase the bioavailability of physiologically active components. The so-called “effervescent” tablets with gas-forming mixtures have found wide application (Shevchenko AM “Methodological aspects of the development of technology for solid instant dosage forms.” Abstract of the thesis for the degree of Doctor of Pharmaceutical Sciences. Pyatigorsk, 2007). However, the term "rapidly dissolving" is understood as the rapid mechanical disintegration of the tablets, and not the complete dissolution of the components of the dry extract in the liquid. The same effect of rapid disintegration is achieved by the recently expanding use of various cross-linked polymers, in particular, crospovidones or croscarmellose sodium (Jagdish Balasubramaniam, Tim B. "The effect of fast acting disintegrants on the dissolution rate of solid oral dosage forms." industry ", No. 4 (21) 2010, pp. 92-99).

The problem is that there is not always a correlation between tablet disintegration and drug dissolution. That is, dispersing solids in a liquid does not accelerate the dissolution of the ingredients (JR Johnson et al., “Effect of Formulation Solubility and Hygroscopicity on Disintegrant Efficiency in Tablets Prepared by Wet Granulation, in Terms of Dissolution,” J. Pharm. Sci. 80 (5), pp. 469-471, 1991). Moreover, in complex complexes, such as extracts of medicinal plants, there are both readily soluble and hardly soluble compounds at the same time. They do not go into solution at the same time. At the same time, both those and others, as a rule, are chemically active substances and can quite easily bind with third-party substances and chemical elements, losing their physiological activity and bioavailability. Therefore, it is important that the compounds pass into a biologically available form quickly and simultaneously and act on the body in a complex manner.

The objective of the present invention is the creation of a drug based on the herb marshmallow, which increases the bioavailability of insoluble and poorly soluble in water medicinal substances of the herb marshmallow extract, accelerates the dissolution of physiologically active compounds.

The technical result is to reduce the disintegration time of tablets in the process of their use while increasing the speed and uniformity of the transition of physiologically active substances from the extract of the herb marshmallow into a bioavailable form (dissolution).

The task is solved, and the technical result is achieved by the fact that a medicinal product based on the herb marshmallow for the treatment of colds and acute respiratory diseases in the form of tablets contains dry extract of the herb marshmallow, calcium phosphate 2-substituted anhydrous, tartaric acid, calcium stearate, crospovidone and a source of C ₁₀ terpenoids with the following amount of ingredients per 1 g in mg:

marshmallow herb extract 10 ... 500 calcium phosphate 2- substituted anhydrous 200 ... 800 wine acid 50 ... 240 crospovidone 95 ... 500 calcium stearate 4 ... 20 source of terpenoids C ₁₀ 1 ... 20.

In the most optimal composition, as a source of terpenoids C ₁₀ contains dry extract of plant seeds and / or essential oils and / or natural food flavors of plant origin, and crospovidone has a particle size of no more than 250 microns.

These features of the invention are essential. Numerous experiments have been carried out with a combination of various compounds that would simultaneously contribute to the rapid and uniform dissolution (transition into a bioavailable form) of physiologically active substances from the extract and, at the same time, would not reduce the therapeutic activity and would not exhibit negative side effects. This effect was achieved by a combination of crospovidone, dibasic calcium orthophosphate, tartaric acid, and various sources of C ₁₀ monoterpenoids. Exclusion from the composition, first of all, crospovidone in combination with a source of monoterpenoids eliminates the manifested effect. The elimination of calcium orthophosphate has less effect, but also reduces this effect. Presumably, an increase in the uniformity and rate of dissolution of a group of physiologically active substances from an extract of the herb marshmallow medicinal, different in their physicochemical properties, is associated with the manifestation as a combination of specific properties of crospovidone, disubstituted calcium orthophosphate and calcium stearate, which have the properties of a disintegrator, stabilizer and emulsifier, on the one hand , and with the properties of the combination of crospovidone and sources of monoterpenoids in the presence of disubstituted calcium orthophosphate and tartaric acid, on the other. Also, as studies and experiments using various sources of monoterpenoids have shown, the presence of a complex of other compounds in these sources (essential oils, fragrances, seed extracts) does not show any negative phenomena that prevent the achievement of the technical result, and in some cases, on the contrary, several enhances the desired effect. In particular, it is known that crospovidones exhibit not only the properties of disintegrators, but also complexing agents and solubilizers that facilitate the dissolution of complex and poorly soluble compounds (E.T. Zhilyakova, A.V. Agarina, M.Yu. Novikova, E.Yu. Timoshenko. "Study of the physicochemical properties of polyvinylpyrrolidone derivatives as thickeners-prolongers in ophthalmic solutions." BelGAU. Scientific Bulletin. Series Medicine. Pharmacy. 2018. Volume 41, No. 2, pp. 338-345; "Polymers BOAI NKY PHARMACEUTICALS LTD.". Pharmaceutical technologies and packaging. No. 2, 2016, pp. 36-39). On the other hand, the high reactivity of monoterpenoids is known, which, due to their conformational flexibility and polyfunctionality, easily enter into a variety of intra- and intermolecular transformations ("Fundamentals of biochemistry of secondary plant metabolism" Textbook. Publishing house of the Ural University. 2014; L.A. Lacerus, A.Yu. Baryshnikov. "Plant terpenoids as possible antineoplastic agents." Russian Biotherapeutic Journal. No. 1, Volume 9, 2010).

The processes of release of various complex organic substances from plant extracts can proceed in different ways, determining the speed and uniformity of dissolution, and further stabilization of solutions. These processes can be influenced by complexes of various factors, which are not yet fully understood. Apparently, the results obtained in the invention showed a synergistic effect of a combination of various properties and factors due to the new composition of the claimed drug. The sources of monoterpenoids are various products, mainly of plant origin. It is known that monoterpenoids are most widely distributed in the plant world. The largest part of monoterpenoids are presented in natural products of plant origin - seed extracts, essential oils, natural flavors (VV Plemenkov. Chemistry of isoprenoids. Chapter 5. Monoterpenes. "Chemistry of plant raw materials", 2006, No. 2. P. 63- 87).

To obtain tablets, the technology of direct compression of a mixture of initial ingredients is used. Due to the similar physicochemical (structure of the crystal lattice, density, solubility) and technological (granulometric composition, bulk density, flowability) properties of the powder components that make up the tablets, it is possible to use the direct compression method. This method makes it possible to exclude the effect of temperature and humidity on the components of the drug during the production of the final product and, thus, to prevent changes in the initial properties of the components during the production of the drug.

The obtained result of the invention was evaluated according to the indicators - the rate and completeness of disintegration of tablets in water and the uniformity and completeness of solubility of the extract components during the disintegration time of the tablets. Disintegration is understood as the deformation of the tablet structure with the transition of the solid phase into an aqueous suspension with possible precipitation. The uniformity and completeness of solubility is understood as the percentage of the release of the active substances of the extract in relation to the qualitative and quantitative content of these components in a standard infusion of the herb marshmallow extract.

To determine the disintegration, a device was used, consisting of a collecting basket, a glass vessel for a liquid with a capacity of 1 liter, a thermostatic device that maintains the required temperature of the liquid, and an electromechanical device that imparts a reciprocating movement to the basket at a distance of at least 50 and not more than 60 mm in the vertical plane at a frequency of 28-32 cycles per minute. The result is assessed visually.

When determining the composition and amount of biologically active substances of the roots of marshmallow medicinal, passed into solution (extractives extracted by water), well-known methods were used - high pressure liquid chromatography (HPLC), UV spectrophotometry and the method of Raman light scattering (RAMAN spectroscopy).

The invention is illustrated by the following examples.

Example 1

Tablets with the composition according to the invention are prepared as follows. After the preparation of raw materials, including sifting and dosing, a premix is prepared by mixing an extract of the herb Althea officinalis with calcium phosphate 2-substituted anhydrous (in a ratio of 1: 1 by weight), tartaric acid and a source of C ₁₀ terpenoids. The resulting premix is sequentially mixed with crosspovidone (maximum particle size 250 μm), the rest of calcium phosphate 2-substituted anhydrous and calcium stearate. The result is a tabletting mass which is directly compressed into tablets weighing 50 grams. The tablets have the shape of a cylindrical circular cross-section with convex bases. In color, the tablets are from light gray to brownish gray interspersed with a lighter and darker gray color and have a characteristic odor of the applied source of monoterpenoids, or, practically, odorless.

To prepare a medicinal product, the ingredients are taken in the following composition and amount in mg per 1 g:

After pressing the composition, light gray tablets are obtained with interspersed gray and the smell of menthol.

Example 2

Tablets were prepared as shown in Example 1, with crospovidone having an average particle size of 50 μm.

To prepare a medicinal product, the ingredients are taken in the following composition and amount in mg per 1 g:

After pressing the composition, light gray tablets are obtained with inclusions of dark gray and the smell of camphor.

Example 3

Tablets are prepared as shown in Example 1, but crospovidone has an average particle size of 150 µm with a maximum size of 250 µm.

To prepare a medicinal product, the ingredients are taken in the following composition and amount in mg per 1 g:

After pressing the composition, light gray tablets with interspersed dark gray, practically odorless, are obtained.

Example 4

Tablets are prepared as shown in Example 1, but crospovidone has an average particle size of 100 μm.

To prepare a medicinal product, the ingredients are taken in the following composition and amount in mg per 1 g:

After pressing the composition, light brown tablets are obtained with inclusions of dark gray and the smell of black currant.

As part of a natural flavoring agent for black currant, monoterpenoids are represented by components related to the biosynthetic types of thujone, carene, pinene, camphene and isocamphene, menthane and acyclic.

Example 5

Tablets are prepared as shown in example 1, but crospovidone has an average particle size of 200 microns, and their maximum size does not exceed 250 microns.

To prepare a medicinal product, the ingredients are taken in the following composition and amount in mg per 1 g:

After pressing the composition, light gray tablets with interspersed dark gray and lemon scent are obtained.

As part of the natural lemon flavoring, monoterpenoids are represented by a wide spectrum, in particular: linalool, borneol, citronellal, geranial, neral, geraniol, etc.

Example 6

The tablets are prepared as shown in example 1.

To prepare a medicinal product, the ingredients are taken in the following composition and amount in mg per 1 g:

After pressing the composition, light gray tablets with interspersed dark gray and a slight smell of peach pits are obtained.

Example 7

The tablets are prepared as shown in example 1.

To prepare a medicinal product, the ingredients are taken in the following composition and amount in mg per 1 g:

The fragrance contains such monoterpenoids as limonene, linalool, geraniol and others. After pressing the composition, gray tablets with interspersed dark gray and the smell of orange are obtained.

Example 8

The tablets are prepared as shown in example 1.

To prepare a medicinal product, the ingredients are taken in the following composition and amount in mg per 1 g:

After pressing the composition, light gray tablets are obtained with interspersed dark gray and anise smell.

Example 9

The tablets are prepared as shown in example 1.

To prepare a medicinal product, the ingredients are taken in the following composition and amount in mg per 1 g:

After pressing the composition, light gray tablets are obtained with inclusions of dark gray and the smell of cloves.

Example 10

The tablets are prepared as shown in example 1.

To prepare a medicinal product, the ingredients are taken in the following composition and amount in mg per 1 g:

After pressing the composition, light brown tablets are obtained with interspersed dark gray and the smell of ginger.

Example 11

The tablets are prepared as shown in example 1.

To prepare a medicinal product, the ingredients are taken in the following composition and amount in mg per 1 g:

Lemon balm flavor contains a wide variety of terpenoids such as geraniol, nerol, citronellol, linalool and others. After pressing the composition, light gray tablets with interspersed dark gray and a lemon-mint smell are obtained.

Example 12

An example is similar to example 10, but as a source of monoterpenoids contains a mixture of eucalyptus essential oil with food flavoring "grapefruit" in a ratio of 1: 5.

Example 13

An example is similar to example 11, but as a source of monoterpenoids contains a mixture of oregano essential oil with food flavoring "bergamot" in a ratio of 1: 4.

Example 14

The tablets are prepared as shown in example 1.

To prepare a medicinal product, the ingredients are taken in the following composition and amount in mg per 1 g:

After pressing the composition, light brown tablets are obtained with interspersed dark gray, with a slight rose scent. Geraniol, citronellol and nerol predominate in the composition of eremotz oil.

Example 15

The tablets are prepared as shown in example 1.

To prepare a medicinal product, the ingredients are taken in the following composition and amount in mg per 1 g:

After pressing the composition, light gray tablets are obtained with inclusions of dark gray and the smell of needles.

Example 16

The tablets are prepared as shown in example 1.

To prepare a medicinal product, the ingredients are taken in the following composition and amount in mg per 1 g:

After pressing the composition, light gray tablets are obtained with interspersed dark gray with a slight specific odor.

Example 17

The tablets are prepared as shown in example 1.

To prepare a medicinal product, the ingredients are taken in the following composition and amount in mg per 1 g:

After pressing the composition, gray tablets are obtained with inclusions of dark gray and a slight characteristic odor.

Example 18

An example is similar to example 17, but as a source of monoterpenoids it contains a mixture of valerian leaf extract with thyme essential oil and dry flax seed extract in a ratio of 1: 0.5: 5.

After pressing the composition, gray tablets are obtained with interspersed dark gray and a characteristic specific odor.

Example 19

An example is similar to example 17, but as a source of monoterpenoids it contains a mixture of peppermint essential oil with food flavoring cinnamon and dry grape seed extract in a ratio of 1: 1: 4.

After pressing the composition, gray tablets are obtained with inclusions of light brown color and a characteristic specific odor.

The drug tablets prepared according to the examples were subjected to disintegration tests in water at room temperature. The results showed that the complete disintegration of the tablets occurred in no more than 3 minutes. Comparative tests of the manufactured preparations "Mukaltin" showed the disintegration time under the same conditions not less than 15 minutes. That is, the rate of "disintegration" of the tablets according to the invention is five times higher than the disintegration rate of the tablets of the compared preparation.

Determination of the composition and amount of physiologically active substances that passed into the solution during the "disintegration" of the tablets, that is, no more than 3 minutes, showed that the completeness of the transition of extractives into the solution is 80-90%.

Thus, the proposed composition of the drug in the form of tablets provides a significant improvement in consumer properties when used for the treatment of colds and acute respiratory diseases.

Claims (4)

1. Medicinal preparation based on the herb marshmallow for the treatment of colds and acute respiratory diseases in the form of tablets, containing dry extract of the herb marshmallow, 2-substituted anhydrous calcium phosphate, tartaric acid, calcium stearate, crospovidone and a source of C ₁₀ terpenoids with the following amount of ingredients in mg per 1 g: marshmallow herb extract 10 ... 500 calcium phosphate 2-substituted anhydrous 200 ... 800 wine acid 50 ... 240 crospovidone 95 ... 500 calcium stearate 4 ... 20 source of terpenoids С ₁₀ 1 ... 20 2. A medicinal preparation according to claim 1, characterized in that as a source of terpenoids C ₁₀ contains essential oils and / or food flavorings and / or dry seed extracts. 3. A medicinal product according to claim 1, characterized in that the crospovidone has a particle size of no more than 250 microns.