BG4347U1 - Silymarin-based colloidal aqueous system - Google Patents

Abstract

The utility model relates to a colloidal aqueous system based on silymarin in liquid and gel form, prepared using only an amphiphilic polyether block copolymer approved for use in food and drugs. The improved water solubility, combined with the beneficial properties of silymarin, make the silymarin-based colloidal aqueous system, in any of the system forms, suitable for use in pharmaceutical, food industry and veterinary medicine applications.

Description

Field of technique

The utility model relates to a colloidal aqueous system based on silymarin in liquid and gel form, prepared using an amphiphilic polyether block copolymer approved for use in food and medicine. The improved solubility in water, combined with the beneficial properties of silymarin, in any of its forms from the system, make it suitable for use in the pharmacy, food industry, human and veterinary medicine and cosmetics.

Prior art

Silymarin is an extract from the seeds of the milk thistle plant Silybum marianum (L). The milk thistle plant belongs to the Asteraceae family. It grows in Bulgaria, in almost every part of the European continent, in North and South America and Australia, in the eastern and southern parts of Iraq, Iran and Afghanistan. It grows on rocky soils and is cultivated well. Silymarin contains several more important compounds with biological activity and a large number of compounds of lesser importance. The main component of silymarin is silybin (80%), which is a mixture of two diastereoisomers, with approximately equal fractions. Other components contained in significant amounts are isosilybin, dehydrosilybin, silychristin, silydianin and taxifolin. In the medical literature, silymarin is discussed as completely harmless, even at very high doses. It is available as a dietary supplement, most commonly to improve liver function.

Scientific publications mention that silymarin has antibacterial, antiviral, antiparasitic, radioprotective and antitumor effects (Katiyar, S. K. Silymarin and skin cancer prevention: Anti-inflammatory, antioxidant and immunomodulatory effects, International Journal of Oncology 2005, 26, 169176 ). Reduces the toxic effect of heavy metals, drugs, organic solvents and mushroom poisons. The extract has a positive effect in viral hepatitis and diabetic patients (Gazaka, R., Walterovab, D., Kren, V., Silybin and Silymarin - New and Emerging Applications in Medicine, Current Medicinal Chemistry, 2007, 14, 315-338).

The main problem for wider application of silymarin is the low water solubility of its bioactive ingredients. This is the reason for low bioavailability and a weaker therapeutic effect. It cannot be administered by injection to patients without increasing its solubility in a physiological environment.

Several different compositions have been developed, in which, mainly with the help of polymers and oligomers, an increase in the water solubility and, accordingly, the bioavailability of silymarin has been achieved. A scientific publication describes a system of modified chitosan, with the help of which the solubility of silymarin in aqueous media is increased by incorporating it into the hydrophobic cores of formed polymeric micelles. (Sui, W., Yin, C, Kong, X., Micellar Solubilization and In Vitro Release of Silymarin in the self-Aggregates of an Amphiphilic Derivative of Chitosan, Macromol. Symp. 2010, 297, 147-153).

Another paper reports a water-soluble form of silymarin obtained by nanoprecipitation with polyethylene sebacate modified with pullulan (Guhagarkar, S. A., Shah, D., Patel, M. D., Sathaye, S. S., Devarajan, P. V., Polyethylene Sebacate-Silymarin Nanoparticles with Enhanced Hepatoprotective Activity, J. Nanosci. Nanotechnol. 2015, 15(6), 4090-3). Both works used modified polymers that are not commercially available, were obtained through multi-step synthetic procedures, and were not approved for use in food or medicine.

A composite consisting of polyvinylpyrrolidone, polyethylene glycol, and silymarin was developed, characterized by the fact that it provides increased solubility of the incorporated silymarin in water compared to the starting powder silymarin (Yousaf, A. M., Malik, U. R., Shahzad, Y. , Mahmood, T., Hussain, T., Silymarin-laden PVP-PEG polymeric composite for enhanced aqueous solubility and dissolution rate: Preparation and invitro characterization, Journal of Pharmaceutical Analysis, 2019, 9, 34-39.). The positive result, however, was achieved with a very large excess of both polymers - 12 times relative to the mass of silymarin.

A water-soluble form of silymarin was obtained by forming an inclusion complex with cyclodextrin (patent CA 2027133 C). In the process of preparing the form, however, organic solvents such as acetone, cyclohexanone, methyl isobutyl ketone and diethyl ketone are used, as well as aggressive acids such as hydrochloric, phosphoric and sulfuric acids. The lowest cyclodextrin/active substance mass ratio at which a water-soluble form is achieved is 2.5.

A Chinese patent (CN 101810660 B) describes a method for preparing water-soluble silymarin using a cyclodextrin complex. The final product is in powder form and contains not less than 45 wt. % silymarin. Regarding its ultimate solubility in water, the maximum concentration mentioned in the patent is 1 wt. %.

In a Bulgarian utility model (entry no. BG 108881 U, peg. no. BG 866 Y1) a medicinal form, in the form of capsules, containing silymarin has been developed. The product is obtained by mixing the starting raw materials and granulating the powder mixture with a water-ethanol solution of polyvinylpyrrolidone (povidone). After drying, a granular mass is obtained, which is filled into capsules. No mention is made of the solubility of the powder mixture in water.

A composition of water-soluble silymarin was obtained by mixing the active substance with a water-soluble sugar or cellulose derivative, polyvinylpyrrolidone and polysorbate (patent RU 2157225 C2). The final product, in the form of a fine powder, contains no more than 10 - 12 wt. % silymarin. The authors claim that this formulation improves the release rate from a buffered tablet and the bioavailability of silymarin compared to the parent substance.

An increased dissolution rate of silymarin in aqueous media was achieved using a formulation containing glyceryl monooleate as the oil phase, a mixture of polysorbate 20 and polyoxyethylene50-hydrogenated castor oil (1:1) and surfactants (J. S. Woo, T.- S. Kim, J.-H. Park, S.C. Chi, Formulation and Biopharmaceutical Evaluation of Silymarin Using SMEDDS, Arch Pharm Res 2007, 30, 8289). This form of silymarin is suitable for oral use, but cannot be injected.

Patent RU 2504347 C1 relates to an injectable dosage form of silymarin for the treatment and prevention of liver diseases in animals. In addition to silymarin, the formulation contains an organic solvent (dimethylacetamide or 1-methyl-2-pyrrolidone, or Solufor P, or transcutol, or propylene glycol, or ethylene glycol, or glyceroformal, or dimethylsulfoxide), nonionic surfactants, preservative, and cosolvent water. The content of silymarin is 5 wt. %, and of the organic solvent - 25 wt. %.

A water-soluble form of silymarin was obtained using surfactants (glycerol esters of fatty acids, sorbitan esters, polysorbates, sucrose esters, lecithins or their mixtures) and polyols (propylene glycol, glycerol, butanediol, pentanediol, hexanediol and sugar-containing alcohol or mixtures thereof) (international patent application WO 2014095485 A1). The developed compositions have a relatively low content of silymarin (5 wt %), while containing ethanol (up to 10 wt %) and glycerol (up to 55 wt %) in large amounts.

Water-soluble formulations of silymarin containing meglumine, polyvinylpyrrolidone and poloxamer 188 have been developed (Patent CN 100542529 C). The compositions are obtained by an energy-intensive procedure, requiring work at high temperature (60-78°C), and the final product is in a solid crystalline form.

No colloidal aqueous system based on silymarin, in liquid or gel form, is known which is prepared using only an amphiphilic polyether block copolymer and contains all the bioactive constituents of silymarin.

Technical nature of the utility model

The task of obtaining water-soluble silymarin was solved by developing a colloidal aqueous system based on silymarin, in the form of a liquid and in the form of a gel, which is harmless to humans, while at the same time preserving all the beneficial properties of silymarin.

A colloidal aqueous system based on silymarin was obtained using an amphiphilic polyether block copolymer approved for use in food and medicine. The amphiphilic block copolymer is a polyether composed of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO). The amphiphilic polyether block copolymer contains 70 wt. % PEO, and the average molar mass of PPO is 4000 g/mol. No other polymer additives or surfactants were used.

The colloidal water system was prepared by means of physical interactions without any chemical modification reaction. In an aqueous medium, the amphiphilic polyether block copolymer self-associates and forms nanosized micelles composed of a hydrophilic shell and a hydrophobic core, in which the lipophilic components of silymarin are immobilized by means of hydrophobic interactions (Figure 1). The colloidal system (in liquid and gel form) is clear, with a yellowish tinge, at the investigated copolymer/silymarin mass ratio of 5 to 2. In the absence of copolymer, or at a copolymer/silymarin ratio lower than 2, a cloudy suspension is formed and after a few days a precipitate of silymarin was observed. Figure 2 shows the permeability of aqueous solutions/suspensions as a function of the copolymer/silymarin ratio, at a constant silymarin concentration of 3 wt. %.

The utility model relates to a colloidal system based on silymarin in the form of a liquid in which the concentration of silymarin is from 2 to 6 wt. %, at a minimum mass ratio of copolymer/silymarin of 2. The maximum concentration of silymarin in the liquid form at this ratio of copolymer/silymarin cannot exceed 6 wt. %. The liquid form is stable for months, does not settle, and its turbidity increases with increasing concentration (Figure 3).

The utility model also relates to a colloidal system based on silymarin in the form of a gel, with a silymarin concentration of 7 wt. % and a copolymer/silymarin mass ratio of 2. The gel can be diluted with water, which preserves the solubility of silymarin.

The advantages of the developed silymarin-based colloidal system, both in liquid and gel form, are that it contains only silymarin, water and a copolymer that is approved for use in food and medicine. The achieved solubility of silymarin in water is much higher compared to other known forms, and the copolymer content is relatively low. The colloid system in the form of a liquid can be administered parenterally, orally, in the form of a spray, drops, tablets. In the form of a gel, it can be applied dermally. This makes the colloidal system based on silymarin, in any of its forms, suitable for use in the pharmaceutical, food industry and veterinary medicine.

Examples of implementation of the utility model

The present utility model is illustrated by the following non-exhaustive examples.

Example 1.

Liquid form of a colloidal water system based on silymarin, with a concentration of 2 wt. % and a copolymer/silymarin ratio of 2, was prepared by dissolving silymarin in ethanol (0.4 g. in 10 ml.). Add 0.8 g of copolymer and stir on a magnetic stirrer at a temperature of 40°C. After dissolving the copolymer, 20 ml of deionized water was added with stirring. The liquid is then placed on a vacuum evaporator and the ethanol is evaporated. The resulting liquid form is yellow-orange in color. Following the same procedure, liquid samples were obtained at copolymer/silymarin ratios of 3, 4 and 5.

Example 2.

A colloidal aqueous system based on silymarin, in the form of a gel, was prepared as follows: 1.4 g of silymarin were dissolved in ethanol (10 ml). Add 2.8 g of copolymer and stir on a magnetic stirrer at a temperature of 40°C. After dissolving the copolymer, 20 ml of deionized water was added with stirring. The liquid was then placed on a vacuum evaporator and the ethanol was evaporated until a gel was formed.

Explanation of the attached figures

Figure 1: Size distribution of silymarin-incorporated polymeric micelles. The sample was prepared at a copolymer/silymarin ratio of 2 and a silymarin concentration of 2 wt. %. A digital photograph of the colloidal system in liquid form is presented in the gadget.

Figure 2: Permeability of aqueous silymarin solutions/suspensions as a function of copolymer/silymarin ratio, at a constant silymarin concentration of 3 wt. % measured at a wavelength of 500 nm. A digital photograph of the solutions/suspensions is presented in the insert.

Figure 3: Transmittance of aqueous silymarin solutions/suspensions as a function of silymarin concentration measured at a wavelength of 500 nm. Copolymer/silymarin mass ratio 2.

Claims (2)

A colloidal aqueous system based on silymarin in the form of a liquid, characterized in that it includes a copolymer and silymarin, the concentration of silymarin being 2 - 6 wt. %, the copolymer/silymarin mass ratio is 5 to 2 A colloidal aqueous system based on silymarin in the form of a gel, characterized in that it includes a copolymer and silymarin, the concentration of silymarin being 7 wt. %, the copolymer/silymarin mass ratio is 5 to 2