RU2155071C1 - Method of medicinal phytofilm preparing - Google Patents

Abstract

FIELD: chemical- -pharmaceutical industry, phytotherapy. SUBSTANCE: invention relates to production of medicinal phytofilms of prolonged effect used for prophylaxis and treatment of inflammatory diseases of body mucosa and skin and immune disorders also. Gelatin, glycerol, methylcellulose, dimethylsulfoxide and polyvinylpyrrolidone are used as accessory substances. The aqueous-spirituous extracts of medicinal substances of the following medicinal plants are used: purple coneflower herb, spotted milk thistle fruits, different species of poplar buds, lavender flowers, medicinal sage leaves, drooping birch buds, pot-marigold flowers, common balm herb, glabrous licorice roots, common lilac bark, snowdon rose rhizomes, estragon herb and horse-mint herb in the following ratio of components, wt.%: aqueous-spirituous extracts, 8-30; gelatin, 2.4-6; methylcellulose, 1-5; dimethylsulfoxide, 0.1-3.5; glycerol, 0.5-4.0; polyvinylpyrrolidone, 0.1-2; and purified water, up to 100. EFFECT: improved adhesive and prolonged properties, increased bioavailability of medicinal phytofilms. 18 dwg, 1 tbl, 1 ex

Description

 The invention relates to the chemical-pharmaceutical industry, in particular to the production of prolonged-release medicinal phytofilms for the prevention and treatment of inflammatory diseases of the mucous membrane and skin of the body, as well as immune disorders.

 In pharmaceutical technology, a known method for producing film dosage forms from individual dosage components and plant substances [11]. However, the film base does not include polyvinylpyrrolidone (PVP) and dimethyl sulfoxide (DMSO), which give the films greater strength and density, adhesion (adhesive force), and prolonged and osmotic properties.

 For the prototype of the invention, we have taken a method of obtaining a means for treating the oral mucosa [11] using aqueous, water-ethanol extracts from medicinal plants — Manchurian aralia, high zamanicha, Schisandra chinensis, safflower-lefthanda, Rhodiola rosea, prickly eleutherococcus, tincture of ginseng, as well as film former (sodium carboxymethyl cellulose, gelatin, sodium alginate, agar-agar), a plasticizer (glycerin) and purified water [11]. It should be noted that this tool contains gelatin and other film-forming agents, but does not contain DMSO, which has a penetrating property due to the active transport of biologically active film compounds into deeper tissues of the body. In addition, the specified composition does not contain PVP, which contributes to an increase in the osmotic properties of the film, solubilization of hydrophobic extractives, increases the bioavailability of the dosage form and the adhesion of the film to the substrate and provides a cleansing effect on the wound. The disadvantage of this method is also the fact that the water-alcohol extracts used in it have mainly tonic properties, but are deprived of the pronounced antimicrobial, anti-inflammatory properties that are shown in the treatment of inflammatory diseases of the mucous membrane and skin of the body.

 The aim of the invention is to expand the range of medicinal phytofilms with more pronounced adhesive and prolonging properties, as well as greater bioavailability.

This goal is achieved by the fact that, as adjuvants, along with gelatin and glycerin, methyl cellulose (film former), DMSO (penetrator) and PVP (osmotically active agent) are used, and water-alcohol extracts from the herb Echinacea purpurea are used as medicinal substances spotted milk thistle fruits, or buds of various types of poplar, or spikelet lavender flowers, or medicinal sage leaves, or hanging birch buds, or medicinal calendula flowers, or lemon balm herb, or root her licorice, or the bark of common lilac, or rhizomes of Rhodiola rosea, or tarragon grass (tarragon), or monarda grass. At the same time, aqueous solutions of film-forming agents are separately prepared, since gelatin swells in cold water, and MC - in hot and dissolve when heated and in cold, respectively. A solution consisting of DMSO, glycerol and PVP is added to the MC solution, homogenized, water-alcohol extracts are added, and again mixed. A gelatin solution is added at a temperature of 37-40 ^° C. and mixed. To remove air from the cooked mass - at the same temperature - ethyl alcohol is added, the mixture is kept in an open container for 1 hour. After this time, the mass is slowly mixed and poured onto glass substrates, previously defatted with alcohol. Dry with a stream of air with a temperature of 25-30 ^o C to a residual moisture content of 5%.

 A search by the applicant for scientific, technical and patent sources of information and a prototype selected from the list of analogues [11] made it possible to identify distinctive features in the claimed technical solution. Therefore, the claimed method of obtaining satisfies the criteria of the invention of "novelty."

 The applicant conducted an additional search for known technical solutions [8-10, 12-14] in order to detect in them features similar to those of the distinctive part of the formula of the claimed production method, showed that these signs are absent, therefore, the claimed technical solution meets the criterion of "inventive step" "

 The inventive method is illustrated by the following example.

Example 1. In a conical flask with a capacity of 50 ml is placed 1.9 (wt.%) MC, pour it with 18 ml of purified water at a temperature of 90 ^o C and left to swell for 2 hours. To the swollen MC add 18 ml of purified room temperature water and kept in the cold until a clear solution is obtained. 3.85 gelatins are placed in another conical flask with a capacity of 50 ml, 15 ml of purified water at room temperature are poured and left to swell for 30-40 minutes. Then add 20 ml of purified water and heat in a water bath until the gelatin is completely dissolved.

The prepared MC solution is placed in the mixer; a mixture of 2.31 glycerol, 1.54 PVP and 0.15 DMSO is added to it with stirring. Then, 19.25 water-alcohol extracts from the medicinal plant material are added: purple coneflower herb or spotted thistle fruit, or various types of poplar buds, or spikelet lavender flowers, or medicinal sage leaves, or hanging birch buds, or medicinal calendula flowers, or herbs lemon balm, or licorice roots, or bark of common lilac, or rhizomes of Rhodiola rosea, or tarragon wormwood (tarragon), or monarda grass. With stirring, the mixture is heated in a water bath to a temperature of 37-40 ^o C and pour in a solution of gelatin. To remove air bubbles from the prepared film mass, add 30 ml of 40% ethanol and incubate for 1 hour. After the specified time, the film mass is carefully homogenized and poured onto a glass substrate, previously degreased with alcohol, with an area of 553 cm ³ . Dry with a stream of air with a temperature of 25-30 ^o C to a residual moisture content of 5%. After drying, films of various sizes are obtained:
- for application to the oral mucosa - 0.8x2 cm, 0.5x2 cm;
- for use in gynecology and dermatology - 2x2 cm;
- according to the doctor’s prescription, films can have other sizes.

 To increase the dosage, in agreement with the doctor, additional doses of the film can be glued.

 Examples of other optimal ratios are given in the table (compositions 1-12). The technology for the manufacture of medicinal films was carried out analogously to example 1.

 A change in the quantities (transcendental parameters) of film-forming agents (MC, gelatin) and auxiliary substances (PVP, DMSO, glycerin) in the direction of decreasing or increasing (transcendental parameters) with respect to those indicated in the table does not lead to a positive effect: the films obtained do not correspond to technological and biopharmaceutical requirements - low stickiness, lack of prolonged action, low bioavailability (DB).

 To study the effect of excipients (BB) and the base on the release of active substances (DV) from medicinal phytofilms, two dosage forms based on typical hydrophilic substances — water-alcohol extracts from the herb Echinacea purpurea (“Echinaplen”) and rhizomes of Rhodiola rosea (“Rosoplen”) were taken "), as well as two leforms based on characteristic hydrophobic substances - water-alcohol extracts from poplar buds (" Topoplen ") and spotted milk thistle fruits (" Siliplen "). The method of dialysis through a semipermeable membrane was used.

In the experiment, glass tubes with an inner diameter of 2.5 cm were used, one end of which was blocked by a semipermeable membrane, which is cellophane. A section 2.5 cm in diameter was cut from the films and placed in dialysis tubes on the membrane, avoiding air entering between the film and the membrane. Dialysis tubes with film samples were placed in a beaker thermostatically controlled at a temperature of 37 ± 1 ^o C with a capacity of at least 400 ml and fixed so that the membranes only came into contact with the surface of the dialysis fluid, which was purified water in a volume of 50 ml. Samples were taken after 2, 5, 10, 15, 20, 25, 30, 40, 50, 60, 90, 120, 150, 180, 210, 240, 270, 300 minutes. The sample volume was 5 ml, after which the sampled volume was immediately replenished with an equal volume of purified water.

The analysis of the active substance content in the dialysis fluid was carried out spectrophotometrically on an SF-26 spectrophotometer in the UV region at a wavelength of 330 nm (for Ekhinaplen), 252 and 279 nm (for Rozoplen), 289 nm (for Topoplen and
“Siliplain”) and a layer thickness of 10 mm [1-7, 15, 16]. The reference solution was purified water.

 In parallel, the optical density of dialysis fluids from films prepared only from the base (placebo) and not containing alcoholic extracts from plants was measured. As the results showed, in these solutions there are practically no substances capable of significantly changing the optical density of the solution. It ranged from 0.025 to 0.075 for all similar studied solutions, which was a statistically significant difference with p ≥ 0.95.

 The research results are shown in FIG. 1-18.

 The dependence of the database on the ratio of film former was investigated (Fig. 1-5). As can be seen from the drawings, MC as a component more readily soluble in comparison with gelatin (G) promotes faster (but not maximum) release of pinostrobin derivatives [5], silybin [3, 4] and salidroside [1, 5] (Fig. . 3 - 5). The release of chicoryic acid [5, 6] and rosavin [1, 5] from gelatin-free phytofilms reaches a maximum much later than gelatin-containing films (Figs. 1, 3).

 Gelatin promotes the release of DV for a long time, but at a low level, so its combination with MC is necessary. This is characteristic of all studied phytofilms (Figs. 1–5).

 A change in release in the direction of increasing the concentration of DV, reducing the time to reach a maximum, increasing the release period at the maximum level is observed in the series of ratios of MC to gelatin 1: 6-1: 4-1: 2.

 Thus, the introduction of film formers (MC: G) in these ratios contributes to the production of a framework whose structure is most optimal for the release of DW.

 The effect of DMSO on the release of DV from phytofilms was clarified (Fig. 6–9). As can be seen from the above graphs, the effect of DMSO is ambiguous on the release of DW from phytofilms. With a decrease in the concentration of DMSO, the release of DV from all phytofilms increases, the time to reach a maximum sharply changes only for Topoplen (6.5 hours - 24.2%, 5.5 hours - 1.33%). However, the complete absence of DMSO in the composition of the film leads to maximum release only in the case of “Topoplen” and “Siliplain” (without changing the dynamics) (Fig. 8 - 9). In the case of "Rosoplen" and "Echinaplen" (Fig. 6 - 7), the absence of DMSO leads to a sharp decrease in bioavailability and a change in the dynamics of release. For chicoryic acid and rosavin, a maximum is characteristic in the initial period of exposure, then a sharp decrease in concentration for 1 - 1.5 hours, and then a gradual decrease. Salidroside release is characterized by a maximum at the 60th minute, reaching a plateau and a gradual decrease in the concentration in the dialysis fluid after 210 minutes.

 Using chromatography in a thin layer of sorbent indirect evidence was obtained of the interaction of chicoryic acid, rosavin and salidroside with DMSO. No evidence has been obtained for pinostrobin and its derivatives, and silybin. It is also believed that DMSO is involved in the “crosslinking” of base macromolecules.

 As can be seen from FIG. 10-14, PVP affects the release of DV from all phytofilms. With a decrease in the PVP content in Ekhinaplen films, the release of phenylpropanoids increases and reaches its maximum in time earlier (at a concentration of 0.77% by 90 minutes; 13.42% by 150 minutes). However, its exclusion from the composition of the film leads to a decrease in release. The period of a sharp increase in concentration is quickly replaced by a period of sharp drop (both periods last 2.5 hours), then there comes a period of a gradual decrease in the content of phenylpropanoids in the dialysis fluid (Fig. 10).

In the study of the release of DV from phytofilms "Rosoplen", "Siliplan" and "Topoplen", the opposite effect of PVP was found: with a decrease in its concentration, the release of DV is reduced. This can be explained by the greater hydrophobicity of the DW from these films as compared to chicory acid, and PVP acts here as a solubilizer. For phytofilms "Rozoplen", "Siliplan" and "Topoplen" a sufficient concentration of PVP is 3.73%, because a further increase in it does not lead to a statistically significant increase in bioavailability (Fig. 11 - 14),
An unequal degree of influence of PVP on the release of rosavin and salidroside was noted (Fig. 11 - 12). With a decrease in the number of PVP from 13.42% to 1.53%, the release of rosavin decreases by 1.2 times, and salidroside - by 1.3 times. But the release is parallel (the same time to reach the maximum concentration, plateau and lower release) (Fig. 11). However, when PVP is excluded from the composition of the film, the dynamics of release changes and becomes non-parallel. The release of rosavin reaches a maximum of 120 minutes, from 120 to 150 minutes there is a sharp drop in concentration and after 150 minutes a gradual decrease in the concentration of rosavin in the dialysis fluid. Salidroside release reaches a maximum of 180 minutes and reaches a plateau, a decrease in concentration is observed after 5 hours of exposure (Fig. 12).

 The effect of PVP on the release of flavolignans from Siliplain and flavonoids from Topoplen is identical (Figs. 13-14). A decrease in PVP leads to a decrease in the maximum concentration of substances in the dialysis fluid and an increase in the time to reach the maximum concentration.

 In the study of extracts from phytofilms using chromatography in a thin layer of sorbent, indirect evidence was obtained of the lack of interaction between PVP and any of the investigated DWs (there are no new spots).

 During the experiment, the effect of glycerol on the release of DV from phytofilms was clarified (Figs. 15-18). With an increase or decrease in the concentration of glycerol in the basis of the database of all studied films, it does not statistically significantly change. However, in the complete absence of glycerol in the film, the release sharply decreases and its dynamics slightly changes (in the direction of increasing the time to reach the maximum). This result can be explained by the softening effect of glycerol on the film, as a result of which the adhesion of the film to the mucous membrane or skin increases, and the contact surface increases. The solubilizing properties of glycerol were also noted.

 With an increase in the concentration of glycerol in Topoplen (Fig. 17), statistically significant changes in the dynamics of release do not occur. However, with the exclusion of glycerol from the film, the release increases 1.05 times at 6 hours of exposure, compared with a film containing 22.9% glycerol. Obviously, this is due to the pronounced hydrophobicity of the pinostrobin derivatives.

 Thus, it is rational to introduce glycerin in a concentration of from 9.0% to 30.0%, a decrease in its amount results in brittle films, and an increase in it is very sticky and non-elastic.

 The results of these studies made it possible to justify the optimal concentration of excipients and components of the base of medicinal phytofilms (table).

Thus, the use of the proposed method for producing medicinal phytofilms gives the following advantages:
1. Medicinal phytofilms obtained by the claimed method have a wider spectrum of biological activity (antimicrobial, anti-inflammatory and immunomodulatory effects), which allows them to be used for the effective treatment of inflammatory diseases of the mucosa.

 2. Medicinal herbal films obtained by the claimed method have more pronounced adhesive and prolonging properties and greater bioavailability.

 3. Using the proposed method, medicinal phytofilms can be produced both in industrial conditions on the basis of pharmaceutical factories and other pharmaceutical enterprises, and in the conditions of pharmacy production, which creates a good basis for expanding the range of medicines used in dentistry, gynecology and dermatology.

Sources of information
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 2. Zapesochnaya G. G., Kurkin V. A., Boyko V. P., Kolkhir V. K. Phenylpropanoids - Promising Natural Biologically Active Substances of Medicinal Plants / Chem-Pharmac. Journal. - 1995. - T. 29, N 4. - S. 47-50.

 3. Kurkin V. A., Zapesochnaya G. G., Avdeeva E. V., Sentsov M. F., Smolyakova I. B., Braslavsky V. B., Pervushkin S. V., Tsybulko S. V. Quantitative determination of silybin and the sum of flavolignans in the fruits of Silybum marianum (L.) Gaertn. // Plant resources. - 1996. - T. 32, no. 3. - S. 80-86.

 4. Kurkin V.A., Lebedev A.A., Avdeeva E.V., Zapesochnaya G.G., Pervushkin S.V., Simerzina L.V., Bulatova M.V. The method of obtaining the extract of milk thistle. - RF patent N 2102999.- A 61 K 35/78, A 61 K 9/08. - 01/27/98, Bull. N 3.

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 6. Kurkin V.A., Avdeeva O.I., Avdeeva E.V., Mizina P.G. Quantification of the amount of hydroxycinnamic acids in the aerial part of Echinacea purpurea (L.) Moench. // Plant resources. - 1998. - T. 34, no. 2. - S. 81-85.

 7. Kurkin V.A., Zapesochnaya G.G., A.V. Mytsyk, A.V. Kurkina, K.S. Pimenov, M.S. Maryina. Flavonoids of the aerial part of Artemisia dracunculus L., cultivated in the Samara region // Plant resources. - 1996. - T. 32, no. 1-2. - S. 88-92.

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Claims (1)

 A method of obtaining medicinal phytofilms, including the use of gelatin (film former), glycerol (plasticizer), water-alcohol extracts of medicinal plants and purified water, characterized in that the method is carried out using methyl cellulose (MC 16, 35, 65 and 100), polyvinylpyrrolidone (PVP ), dimethyl sulfoxide (DMSO) and water-alcohol extracts from the herb Echinacea purpurea, or the fruits of the thistle spotted, or the buds of various types of poplar, or the flowers of spikelet lavender, or the leaves of medicinal sage, or kidneys hanging cuts, or flowers of calendula officinalis, or herbs of lemon balm, or licorice roots, or ordinary lilac bark, or rhizomes of Rhodiola rosea, or tarragon wormwood, or monarda grass in the following ratio of components, wt. %: water-alcohol extracts from the herb Echinacea purpurea, or the fruits of the thistle spotted, or the kidneys of various types of poplar, or the flowers of spikelet lavender, or the leaves of medicinal sage, or the buds of the birch bud, or the flowers of the calendula officinalis, or the herbs of the lemon balm, or licorice roots naked, or bark of common lilac, or rhizomes of Rhodiola rosea, or wormwood tarragon (tarragon), or monarda grass - 8 - 30; gelatin 2.4 - 6.0; methyl cellulose 1 to 5; dimethyl sulfoxide 0.1-3.5; glycerol 0.5 to 4.0; polyvinylpyrrolidone 0.1-2.0; purified water - up to 100.

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