RU2448731C2 - Phospholipid composition - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical and cosmetic industry and medicine. Claimed invention relates application for transdermal delivery of biologically active substances of liquid crystals of phospholipids in system phospholipid concentrate- petrolatum - water in area of component concentration ensuring formation of liquid-crystal structure. Composition contains phospholipid concentrate in amount 45-83% (weight), petrolatum in amount 5-45% (weiht) and water in amount 5-40% (weight). It is possible to introduce significant amounts of oil- and water-soluble biologically active substances, sufficient for manifestation of their pharmacological activity, into elaborated composition.

EFFECT: obtaining novel chemical-pharmaceutical composition.

8 ex, 5 tbl, 1 dwg

Description

The invention relates to the field of medicine and cosmetics, namely to means of transdermal drug delivery. Promising carriers for the targeted transport of drugs into the body are nanostructures of lecithin (phosphatidylcholine) and other natural phospholipids. Lecithin-based nanomaterials for medicine have such advantages as non-toxicity and biocompatibility, the ability to solubilize biologically active substances, and the ability to accelerate transport through the skin. This makes them attractive for widespread use. An additional advantage of phospholipid nanostructures is the possibility of creating, on their basis, sustained release drugs with controlled release of the drug substance.

A large number of drugs based on phospholipid liposomes have been developed and patented, some of them are already at the stage of clinical trials and certification, some drugs are already on the market. The lecithin organogels existing in the lecithin - nonpolar organic solvent - water systems in the region of low water concentrations are proposed and patented as nanomaterials for the targeted transport of medicinal substances.

The main disadvantage of liposome preparations is their low storage stability, since liposome suspensions are lyophobic colloidal systems, that is, they are not thermodynamically stable. Lecithin organogels, on the contrary, are thermodynamically stable, however, they also have a serious drawback - the low ability to solubilize water and water-soluble substances. This creates difficulties when introducing into the gel water-soluble biologically active substances in the desired concentration. Liquid crystals are thermodynamically stable structures of phospholipids that can exist in water-oil-surfactant systems in the range of medium water concentrations.

Numerous scientific articles are known in which liquid crystals were studied in lecithin-water systems, including in the presence of hydrocarbons. For example, the structure formation of lecithin in water and polar and nonpolar organic media, including the formation of liquid crystals, is considered in a review by Yu.A. Shchipunov [Schipunov Yu.A. Self-organizing structures of lecithin // Advances in Chemistry. - 1997. - T. 66, No. 4. - S. 328-352].

We propose using liquid crystals of phospholipids existing in the system of phospholipid concentrate - paraffin oil - water as the basis for cosmetic and medical products for external use. The use of affordable phospholipid concentrates to obtain liquid crystals makes the proposed base economically attractive.

Known composition with controlled release for the introduction of biologically active materials, described in international patent WO 84/02076 S. Engstrom, K. Larsson, B. Lindman "Method of preparing controlled-release preparations for biologically active materials and resulting composition" from 01.06.84 (IPC: A61K 9/22, 9/10, 9/00). Describes a composition for the controlled release of biologically active substances, containing amphiphilic surfactants capable of forming a liquid crystalline phase in an aqueous medium. The composition may include monoglycerides, phospholipids and galactolipids as amphiphilic substances, and water, glycerin, ethylene glycol and propylene glycol as a polar component. A non-polar organic solvent (i.e. oil) is not included in the composition of the described composition, which distinguishes it from the present invention.

Known means for improving skin regeneration described in the international patent WO 2006118245 Yamaguchi Yoko and Igarashi Rie "Skin regeneration promoter" from 11/09/2006 (IPC A61K 8/39). The composition of the claimed funds includes the active substance (for example, retinol, retinoic acid, their derivatives), included in the liquid crystal base. The base is a lyotropic liquid crystal containing 5-80% (wt.) Surfactant and 5-80% (wt.) Water. Among other surfactants capable of forming lyotropic liquid crystals, lecithin is mentioned in the application. The described lyotropic liquid crystal may contain 1-80% (wt.) Oil, squalene is mentioned as an oil. However, oil is not a necessary component of this composition, which distinguishes it from the present invention.

An analogue of the claimed invention is patent RU 2201747 by S. B. Anderson, S. Yonne, T. Landh "Composition replacing tobacco (options), method for producing it, method for treating smoking, method for treating Alzheimer's disease, Parkinson's disease or ulcerative colitis" from 09/15/1998 (IPC A61K 9/00), which is a translation of the international patent WO 99/15171. The invention describes a tobacco replacement composition containing an active substance (nicotine) and one or more polar lipids and one or more anionic surfactants in quantities sufficient to form a liquid crystal phase or its precursor or secondary product when placed in a polar solvent. As a polar solvent, aqueous solutions, glycerol or propylene glycol or a mixture thereof are described, polar lipids are monoglycerides, anionic surfactants are fatty acids. Lecithin and other phospholipids, as well as paraffin oil, are not mentioned in this invention.

Other liquid crystal compositions for external use are known, for example, JP patent 2009029740 (Japan) Nakajima Atsushi, Ueno Toshiya, Horie Kiyoshi "Liquid crystal composition containing phytosterol ester and cosmetic or external preparation for skin containing the same" dated 12.02.2009 (IPC A61K 8 / 63), which describes a liquid crystal composition containing esters of phytosterol and saturated monobasic fatty acids. In KR patent 20080065726 (South Korea) Lee Kwang Sik, Lee Seung Ji, Lee Ghang Tai, Lee Sang Gil, Lee Kun Kook "Cosmetic composition for protecting skin containing traditional herb medicine contained in liquid crystal base" dated July 15, 2008 (IPC A61K 8/97) proposes a composition containing 0.1-60.0% (wt.) A mixture of plant extracts and 20.0-99.9% (wt.) Of a natural liquid crystal base containing lecithin, ceramide, cholesterol and their derivatives, and phytosterol and its derivatives. CN patent 101473933 (China) Zhengwu Wang, Xiuhua Yan, Shujun Xu "Beta-carotene LCD vector and preparation method thereof" dated 08.07.2009 (IPC A23L 1/275) describes a liquid crystal carrier for beta-carotene, which includes 10-65% (wt.) surfactant EL-35, 4-54% (wt.) ethyl butyrate, the rest is water. The listed compositions also do not contain non-polar organic (oil) component.

The closest in technical essence (prototype) of the claimed invention is a lecithin organogel containing an organic solvent, water and lecithin and physiologically active substances, characterized in that vaseline or high vacuum oil in a concentration of 73.81-97.66% is used as an organic solvent ( wt.), lecithin - in a concentration of 2.27-18.82% (wt.), and water is contained in a concentration of 0.07-7.37% (wt.) [Patent RU No. 2155604 (Russia), E.V. .Yurtov, N.M. Murashova “Lecithin Organogel” dated 10.09.2000, IPC A61K 47/24, 31/685, 7/00].

The composition claimed in this patent contains water and phospholipid (lecithin) in a lower concentration, and liquid paraffin or high vacuum oil is in a higher concentration than the proposed product, which determines the difference in the resulting nanostructures - the prototype is an organogel made of interwoven lecithin reverse micelles.

The technical result of the invention is to increase the solubilization capacity of the composition with respect to water and water-soluble substances (compared with the prototype) and the formation of a liquid crystal structure.

The technical result is achieved by a composition containing a phospholipid concentrate in an amount of 45-83% (wt.), Liquid paraffin in an amount of 5-45% (wt.) And water in an amount of 5-40% (wt.).

Obtaining liquid crystals in the system of phospholipid concentrate - liquid paraffin - water includes the following operations:

- dissolution of a sample of phospholipid concentrate in liquid paraffin,

- adding to the resulting solution of water and water-soluble components and their solubilization.

Example 1

5.50 g of a phospholipid concentrate and 2.35 ml of liquid paraffin were introduced into a conical flask and kept in a closed flask at 70 ° C for 3.5 hours with stirring until a homogeneous system was obtained. Then, 2.50 ml of distilled water was added to the sample. The solubilization of water was carried out in a closed flask at a temperature of 40 ° C and with stirring for 3 hours. The resulting sample contains 55% (wt.) Phospholipid concentrate, 25% (wt.) Distilled water, 20% (wt.) Liquid paraffin. The resulting liquid crystals are stable and can be stored in a closed vessel for several months.

To obtain liquid crystals, the Moslecitin phospholipid concentrate was used (State Research Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Russia) containing a phospholipid complex — 97% (wt.), Including phosphatidylcholine (lecithin) —22% (wt.). This phospholipid concentrate is a biologically active food supplement and is recommended as an additional source of phospholipids.

The presence or absence of a liquid crystal structure and its type were determined by polarization microscopy using an Axiostar plus microscope for observation in transmitted light (Zeiss, Germany) with a Canon digital camera.

Figure 1 is an example of a micrograph through crossed polaroids of lyotropic liquid crystals of a lamellar structure, obtained in the system of phospholipid concentrate "Moslecitin" - vaseline low - water. The sample contains 55% (wt.) Moslecitin phospholipid concentrate, 20% (wt.) Liquid paraffin and 25% (wt.) Water. The microphotograph shows the fan texture of the sample, characteristic of liquid crystals of the lamellar structure.

Example 2

The dissolution of the phospholipid concentrate in oil and the solubilization of water was carried out according to the method described in example 1. The presence of a liquid crystal structure was checked by polarization microscopy, as described in example 1. Table 1 shows the composition of the samples obtained in the system of phospholipid concentrate "Moslecitin" - vaseline oil - water at 20 ° C, and the presence of their liquid crystal structure. As can be seen from the data presented, the ranges of the content of the components indicated in the claims correspond to the region of existence of liquid crystals in the system of phospholipid concentrate - liquid paraffin - water.

Table 1 The composition and structure of the samples obtained in the system of phospholipid concentrate "Moslecitin" - liquid paraffin - water at 20 ° C. Sample No. The content of components,% (wt.) Structure Phospholipid concentrate Vaseline oil Water one 45 thirty 25 Liquid Crystal (LCD) 2 83 9 8 LCD 3 66 fifteen 19 LCD four 74 5 21 LCD 5 45 45 10 LCD 6 62 twenty eighteen LCD 7 76 19 5 LCD 8 54 6 40 LCD 9 70 10 twenty LCD 10 55 twenty 25 LCD eleven fifty 0 fifty Two phases (suspension of phospholipid vesicles in water) 12 40 57 3 Lecithin Organogel 13 90 5 5 Two phases (FA and solid phospholipid) fourteen 40 thirty thirty Two phases (emulsion of droplets of an oil phase in water)

Example 3

6.60 g of SIGMA phospholipid concentrate and 1.76 ml of liquid paraffin were added to the conical flask. Soya lecithin (SIGMA, USA) - a preparation of purified soybean phospholipids with a content of phosphatidylcholine (lecithin) of 40% (wt.). A portion of the phospholipid concentrate was dissolved in liquid paraffin at a temperature of 90 ° C for 5 hours with stirring. The process was carried out at 90 ° C, since at 80 ° C the dissolution occurs very slowly, and at a higher temperature, lecithin decomposes intensively. The resulting solution was cooled to 50 ° C. and 1.90 ml of distilled water was added. To avoid evaporation, water was solubilized in a hermetically sealed flask at a temperature of 50 ° C for 5 hours with stirring. The presence of a liquid crystal structure was checked by polarization microscopy as described in Example 1. A homogeneous liquid crystal sample was obtained that contains 66% (wt.) SIGMA phospholipid concentrate, 15% (wt.) Liquid paraffin and 19% (wt.) Water.

Example 4

6.60 g of Our Lecithin phospholipid concentrate and 1.76 ml of liquid paraffin were added to the conical flask. The phospholipid concentrate “Our Lecithin” (LLC “Yuviks-farm”, Russia) contains essential sunflower phospholipids - 98.6% (wt.), Monoglycerides - 0.8% (wt.) And water - 0.6% (wt. ) This phospholipid concentrate is a biologically active food supplement and is recommended as an additional source of phospholipids. A portion of the phospholipid concentrate was dissolved in liquid paraffin at a temperature of 70 ° C for 3 hours with stirring. The resulting solution was cooled to 50 ° C. and 1.90 ml of distilled water was added. To avoid evaporation, water was solubilized in a hermetically sealed flask at a temperature of 50 ° C for 2 hours with stirring. The presence of a liquid crystal structure was checked by polarization microscopy, as described in Example 1. A homogeneous liquid crystal sample was obtained, which contains 66% (wt.) Phospholipid concentrate “Our Lecithin”, 15% (wt.) Vaseline oil and 19% (wt.) Water .

As can be seen from examples 3 and 4, the preparation of liquid crystals in the system of phospholipid concentrate - liquid paraffin - water is possible on the basis of phospholipid concentrates of various compositions obtained from various natural sources.

Example 5

Samples of the compositions in the system of phospholipid concentrate Moslecithin - liquid paraffin - water (organogel from interwoven lecithin reverse micelles and lyotropic liquid crystal) were obtained according to the procedure described in example 1. The solubilization capacity of the samples with respect to water-soluble biologically active substances was studied using glucose as an example . To this end, portions of a 10% (wt.) Aqueous glucose solution were introduced into liquid crystal samples in increments of 1.1-1.2% (wt.) Relative to the weight of the initial samples. Solubilization was carried out in closed vessels at a temperature of 40 ° C and with stirring. During the experiment, the maximum content of the introduced component was determined at which clouding of the sample and destruction of the liquid crystal structure were not observed according to polarization microscopy.

Table 2 presents the results of determining the solubilization capacity of the lecithin gel and liquid crystal with respect to glucose. The concentration of glucose introduced was recalculated relative to the final composition of the samples.

table 2 Solubilization capacity of the compositions in the system phospholipid concentrate - liquid paraffin - water Structure The original composition The amount of solubilized glucose,% (wt.) reverse micelle organogel 40% (wt.) Phospholipid concentrate (corresponding to 8.80% (wt.) Lecithin), 57% (wt.) Liquid paraffin, 3% (wt.) Water 0.20 liquid crystal 66% (wt.) Phospholipid concentrate (corresponding to 14.52% (wt.) Lecithin), 15% (wt.) Liquid paraffin, 19% (wt.) Water 0.67 liquid crystal 82% (wt.) Phospholipid concentrate (corresponding to 18.04% (wt.) Lecithin), 8% (wt.) Petroleum jelly, 10% (wt.) Water 2.45 liquid crystal 53% (wt.) Phospholipid concentrate (corresponding to 11.66% (wt.) Lecithin), 10% (wt.) Liquid paraffin, 37% (wt.) Water 0.54 liquid crystal 50% (wt.) Phospholipid concentrate (corresponding to 11.00% (wt.) Lecithin), 40% (wt.) Petroleum jelly, 10% (wt.) Water 0.81

From the presented data it can be seen that the proposed composition in the form of liquid crystals in the system of phospholipid concentrate - liquid paraffin - water has a significantly greater solubilization capacity in relation to water and water-soluble substances in comparison with the prototype - lecithin organogel.

Example 6

Liquid crystal samples containing 66% (wt.) Moslecitin phospholipid concentrate, 15% (wt.) Petrolatum oil and 19% (wt.) Distilled water were obtained according to the procedure described in example 1. The solubilization capacity of the obtained samples was investigated. in relation to water and oil soluble biologically active substances. Solubilization of hydrophilic substances (water-soluble) was studied using glucose and acetylsalicylic acid as an example; solubilization of hydrophobic substances (oil-soluble) was studied using α-tocopherol acetate (vitamin E) and tea tree essential oil. For this, portions of solutions of the corresponding substances were introduced into samples of liquid crystals in increments of 1.1-1.2% (wt.) Relative to the mass of the initial samples. Solubilization was carried out in closed vessels at a temperature of 40 ° C and with stirring. During the experiment, the maximum content of the introduced component was determined at which clouding of the sample and destruction of the liquid crystal structure were not observed according to polarization microscopy. The obtained data on the solubilization capacity of liquid crystals in the system of phospholipid concentrate - liquid paraffin - water are presented in table 3. The concentrations of the introduced substances were recalculated relative to the final composition of the samples.

Table 3 The solubilization capacity of liquid crystals in relation to some water and oil soluble substances. The composition of the solution introduced into the liquid crystal The amount of injected solution,% (wt.) The amount of biologically active substance introduced,% (wt.) 10% (wt.) Aqueous glucose solution 6.7 0.67 10% (wt.) Solution of acetylsalicylic acid in 1M aqueous sodium hydroxide solution 9.6 0.96 30% (wt.) Solution of α-tocopherol acetate in liquid paraffin 5,0 1,5 100% Tea Tree Essential Oil 16.3 16.3

As can be seen from the data presented in example 6, significant amounts of oil- and water-soluble biologically active substances, sufficient for the manifestation of their pharmacological activity, can be introduced into the developed phospholipid liquid crystal composition. For example, in diseases of the neuromuscular system of α-tocopherol, acetate is prescribed in doses of 50-100 mg per day [M.D. Mashkovsky. "Medicines." A manual on pharmacotherapy for doctors, in two parts. Part 2. ZAO Gamta, Vilnius, 1994. S.33-34], for which 3.4-6.7 g of the developed composition is sufficient. This allows you to use the proposed liquid crystal composition as a basis for medical and cosmetic products.

Example 7

Samples of liquid crystals in the systems phospholipid concentrate "Moslecitin" - liquid paraffin - water and phospholipid concentrate "Moslecitin" - water were obtained according to the method described in example 1. The solubilization capacity of the obtained samples in relation to oil-soluble substances was studied using the oil-soluble dye of Sudan I. B samples of the liquid crystal introduced a portion of the dry dye of Sudan I and dissolved at a temperature of 40 ° C with stirring for 1 hour. Then the sample was cooled to room temperature and examined under a microscope. The experiment was carried out until a dye insoluble in the liquid crystal matrix was detected in the microcrystal sample.

Table 4 Solubilization capacity of liquid crystals in relation to an oil-soluble dye. The initial composition of the liquid crystal The number of solubilized Sudan I,% (wt.) 75% (wt.) Phospholipid concentrate, 25% (wt.) Water 1.3 75% (wt.) Phospholipid concentrate, 13% (wt.) Water, 12% (wt.) Liquid paraffin 2.5

As can be seen from the data presented in table 4, a much more oil-soluble dye can be introduced into a liquid crystal sample containing oil, phospholipid concentrate, and water than into a sample containing only phospholipid concentrate and water. Thus, the introduction of liquid crystal phospholipid composition of liquid paraffin allows you to increase the solubilization capacity of the composition with respect to oil-soluble substances.

Example 8

Samples of liquid crystals in the system of phospholipid concentrate "Moslecithin" - liquid paraffin - water were obtained according to the method described in example 1. The viscosity of liquid crystals was studied depending on the concentration of liquid paraffin with the same ratio of phospholipids and water concentrations.

The rheological properties of the samples were studied using a Rheotest 2 rotational viscometer (Germany) with a cone-plate measuring system in the range of shear rates from 5.56 to 540 s ^-1 . During the measurement, the temperature was controlled using a thermostat with an accuracy of 0.5 ° C. Before each measurement, the sample was kept for 20 minutes at a given temperature. The dependence of the viscosity of liquid crystal samples on the content of liquid paraffin at temperatures of 20 and 40 ° C and a shear rate of 60 s ^{-1 are} presented in table 5.

Table 5 The dependence of the viscosity of samples of liquid crystals on the content of liquid paraffin. Composition,% (wt.) Viscosity, Pa · s phospholipid concentrate Vaseline oil water 20 ° C 40 ° C 74.0 5,0 21.0 25.0 35.0 72.0 7.5 20.5 27.5 35.0 70.0 10.0 20,0 22.5 30,0 66.0 15.0 19.0 9,4 16.3 62.0 20,0 18.0 3.0 10.0 58.0 25.0 17.0 1,6 7.9

Viscosity is an important technological parameter and significantly affects the consumer properties of a finished medical or cosmetic product. As can be seen from the data shown in table 5, the viscosity of liquid crystals in the system of phospholipid concentrate - liquid paraffin - water decreases significantly with increasing oil concentration. Thus, the introduction of vaseline oil into liquid phospholipid crystals allows one to vary the viscosity of the samples over a wide range. This will allow to create on the basis of these liquid crystals medical products with optimal viscosity, which are easily applied to the skin and have the required release rate of drugs.

Claims (1)

A liquid crystal composition for transdermal delivery of biologically active substances, including a phospholipid concentrate, liquid paraffin, and water, characterized in that it contains a phospholipid concentrate in an amount of 45-83 wt.%, Liquid paraffin in an amount of 5-45 wt.% And water in an amount of 5 -40 wt.%.

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