RU2847025C1 - Method of producing phenobarbital nanocapsules - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to chemistry and pharmaceutics and specifically to a method of producing phenobarbital nanocapsules. According to the disclosed method, phenobarbital is slowly added to a suspension of a mixture of chitosan and potato starch in benzene in presence of 0.01 g of an E472c preparation as a surfactant while mixing at 1100 rpm, wherein the weight ratio of phenobarbital (core) : chitosan : potato starch (coating) in terms of dry substance is 4:3:1 or 3:1:2, then adding hexane, obtained suspension is filtered and dried at room temperature.

EFFECT: invention simplifies and speeds up the process of producing phenobarbital nanocapsules in a shell of a mixture of chitosan and potato starch, as well as reduces loss when producing nanocapsules (higher mass output).

1 cl, 12 dwg, 2 tbl, 2 ex

Description

The invention relates to the field of nanotechnology, medicine and veterinary science.

Methods for producing drug microcapsules have been previously known. For example, in Patent No. 2092155 IPC A61K 047/02, A61K 009/16, published on October 10, 1997, the Russian Federation proposed a method for microencapsulating drugs based on the use of specialized equipment irradiated with ultraviolet rays.

The disadvantages of this method are the length of the process and the use of ultraviolet radiation, which can affect the formation of microcapsules.

Patent 2091071 IPC A61K 35/10 Russian Federation published on September 27, 1997 proposes a method for producing a drug by dispersing in a ball mill to obtain microcapsules.

A disadvantage of this method is the use of a ball mill, which can lead to the destruction of some of the microcapsules and, ultimately, to a decrease in the yield of the final product.

In patent 2076765 IPC B01D 9/02 Russian Federation published on 10.04.1997, a method for obtaining dispersed particles of soluble compounds in microcapsules by crystallization from a solution is proposed, characterized in that the solution is dispersed in an inert matrix, cooled and, by changing the temperature, dispersed particles are obtained.

The disadvantage of this method is the complexity of implementation: obtaining microcapsules by dispersion followed by a change in temperature, which slows down the process.

Patent 2101010 IPC A61K 9/52, A61K 9/50, A61K 9/22, A61K 9/20, A61K 31/19 Russian Federation published on 10.01.1998 proposes a chewable form of a medicinal product with taste masking, having properties of controlled release of the medicinal product, containing microcapsules 100-800 μm in diameter and consisting of a pharmaceutical core with crystalline ibuprofen and a polymer coating including a plasticizer, elastic enough to resist chewing. The polymer coating is a copolymer based on methacrylic acid.

Disadvantages of the invention: the use of a copolymer based on methacrylic acid, since these polymer coatings are capable of causing cancerous tumors; the production of microcapsules by suspension polymerization; complexity of execution; the lengthy process.

In patent 2139046 IPC A61K 9/50, A61K 49/00, A61K 51/00 Russian Federation published on 10.10.1999, a method for producing microcapsules is proposed as follows. An oil-in-water emulsion is prepared from an organic solution containing a dissolved mono-, di-, triglyceride, preferably tripalmitin or tristearin, and optionally a therapeutically active substance, and an aqueous solution containing a surfactant, optionally a portion of the solvent is evaporated, a redispersing agent is added, and the mixture is freeze-dried. After freezing, the mixture is then redispersed in an aqueous carrier to separate the microcapsules from residual organic matter, and the hemispherical or spherical microcapsules are dried.

The disadvantages of the proposed method are the complexity and duration of the process, the use of freeze-drying, which takes a lot of time and slows down the process of obtaining microcapsules.

In patent 2173140 IPC A61K 009/50, A61K 009/127 Russian Federation published on 10.09.2001, a method for producing organo-silicon lipid microcapsules using a rotary cavitation unit with high shear forces and powerful hydroacoustic phenomena of the sound and ultrasonic range for dispersion is proposed.

Disadvantages of the proposed method: complexity, duration, use of a high-shear mixer.

In patent 2359662 IPC A61K 009/56, A61J 003/07, B01J 013/02, A23L 001/00 published on 27.06.2009 by the Russian Federation, a method for producing microcapsules using spray cooling in a Niro spray cooling tower under the following conditions is proposed: inlet air temperature of 10°C, outlet air temperature of 28°C, rotation speed of the spray drum of 10,000 rpm. The microcapsules according to the invention have improved stability and provide controlled and/or prolonged release of the active ingredient.

The disadvantages of the proposed method are the duration of the process and the use of special equipment, a set of specific conditions (inlet air temperature 10°C, outlet air temperature 28°C, rotation speed of the spray drum 10,000 rpm).

In patent 20110223314 IPC B05D 7/00 20060101 B05D 007/00, B05C 3/02 20060101 B05C 003/02; B05C 11/00 20060101 B05C 011/00; B05D 1/18 20060101 B05D 001/18; B05D 3/02 20060101 B05D 003/02; B05D 3/06 20060101 B05D 003/06 dated 10.03.2011 US a method for producing microcapsules by suspension polymerization is described, relating to a group of chemical methods using a new device and ultraviolet irradiation.

The disadvantages of this method are the complexity and duration of the process, the use of special equipment, and the use of ultraviolet radiation.

Patent WO/2011/150138 US IPC C11D 3/37; B01J 13/08; C11D 17/00 published on 01.12.2011 describes a method for producing solid microcapsules of water-soluble agents by polymerization.

The disadvantages of this method are the complexity of implementation and the length of the process.

In patent WO/2011/127030 US IPC A61K 8/11; B01J 2/00; B01J 13/06; C11D 3/37; C11D 3/39; C11D 17/00 published on 13 October 2011, several methods for producing microcapsules are proposed: interfacial polymerization, thermally induced phase separation, spray drying, solvent evaporation, etc.

The disadvantages of the proposed methods are the complexity, duration of the processes, as well as the use of special equipment (filter (Albet, Dassel, Germany), spray dryer for collecting particles (Spray-4M8 Dryer from ProCepT, Belgium)).

The closest method is the one proposed in patent 2134967 IPC A01N 53/00, A01N 25/28 published on 27.08.1999 Russian Federation (1999). A solution of a mixture of natural lipids and a pyrethroid insecticide in a weight ratio of 2-4:1 in an organic solvent is dispersed in water, which simplifies the microencapsulation method.

The disadvantage of the method is dispersion in an aqueous medium, which makes the proposed method inapplicable for obtaining nanocapsules of water-soluble drugs in water-soluble polymers.

The technical objective is to simplify and accelerate the process of obtaining phenobarbital nanocapsules in a composite shell of chitosan and potato starch, and to reduce losses during the production of nanocapsules (increase the mass yield).

The solution to the technical problem is achieved by a method for producing phenobarbital nanocapsules, characterized in that a composition of chitosan and potato starch is used as the shell of the nanocapsules when obtaining nanoparticles by non-solvent precipitation using hexane as a precipitant.

A distinctive feature of the proposed method is the production of nanocapsules by non-solvent precipitation using hexane as a precipitant, as well as the use of a composition of chitosan and potato starch as a particle shell.

The result of the proposed method is the production of phenobarbital nanocapsules in a composite shell of chitosan and potato starch.

The yield of nanocapsules is 100%.

EXAMPLE 1. Production of phenobarbital nanocapsules in a composite shell of chitosan and potato starch. The phenobarbital:chitosan:starch ratio is 4:3:1.

4 g of phenobarbital powder are slowly added to a suspension sequentially obtained from 1 g of potato starch and 3 g of chitosan in benzene in the presence of 0.01 g of the drug E472c (a glycerol ester with one or two molecules of edible fatty acids and one or two molecules of citric acid, where citric acid, as a tribasic acid, can be esterified with other glycerides and, as an oxoacid, with other fatty acids. Free acid groups can be neutralized with sodium) as a surfactant while stirring at 1100 rpm. Then 20 ml of hexane are added. The resulting suspension is filtered and dried at room temperature.

8 g of powder were obtained. The yield was 100%.

EXAMPLE 2. Production of phenobarbital nanocapsules in a composite shell of chitosan and potato starch. The ratio of phenobarbital: chitosan: starch is 3:1:2.

3 g of phenobarbital powder are slowly added to a suspension sequentially obtained from 2 g of potato starch and 1 g of chitosan in benzene in the presence of 0.01 g of the drug E472c (a glycerol ester with one or two molecules of edible fatty acids and one or two molecules of citric acid, where citric acid, as a tribasic acid, can be esterified with other glycerides and, as an oxoacid, with other fatty acids. Free acid groups can be neutralized with sodium) as a surfactant while stirring at 1100 rpm. Then 18 ml of hexane are added. The resulting suspension is filtered and dried at room temperature.

6 g of powder was obtained. The yield was 100%.

Appendix 1

EXAMPLES 1-2 Determination of nanocapsule sizes by NTA.

Measurements were performed on a Nanosight-LM10-HS particle size and concentration analyzer (Malvern Instruments Ltd., UK), designed to measure particle size distribution in the submicron range and their concentration. The instrument operates using the nanoparticle tracking analysis (NTA) method described in ASTME 2834. A colloidal solution (the test sample), diluted to a concentration of approximately 10 ⁸ particles/mL, is introduced into the laser module, where it is illuminated by a laser beam. Scattering spots of individual submicron particles are recorded at an angle of 90° using a highly sensitive black-and-white Scientific CMOS video camera. NANOSIGHT NTA 2.3. Analytical software tracks the number of particles in the observation area, as well as the mean square displacement of each observed particle per unit of time. The Stokes-Einstein equation then calculates the particle size and determines the particle concentration.

To determine the size and concentration of nanoparticles, a 0.1-gram sample of powder was taken and dissolved in 10 ml of ultrapure water. After sonication in an ultrasonic bath, 2 ml of the 10 ml suspension was withdrawn into a 2 ml syringe, which was connected to the laser module with a sample chamber.

The determination of the size and concentration of nanoparticles in each type of sample was performed in six replicates (samples).

During the determination of the size and concentration of nanoparticles of a sample of phenobarbital nanocapsules in a composite shell of chitosan and potato starch at a phenobarbital: chitosan: starch ratio of 4:3:1, the average particle size was 29.9 nm at a concentration of 1.33e +008 particles/ml (see Table 1, Fig. 1 - Fig. 6).

During the determination of the size and concentration of nanoparticles of a sample of phenobarbital nanocapsules in a composite shell of chitosan and potato starch at a phenobarbital: chitosan: starch ratio of 3:1:2, the average particle size was 46.28 nm at a concentration of 7.22e +007 particles/ml (see Table 2, Fig. 7 - Fig. 12).

Claims (1)

A method for producing phenobarbital nanocapsules, characterized in that phenobarbital is slowly added to a suspension of a mixture of chitosan and potato starch in benzene in the presence of 0.01 g of the drug E472c as a surfactant with stirring at 1100 rpm, wherein the mass ratio of phenobarbital (core): chitosan: potato starch (shell), when converted to dry matter, is 4:3:1 or 3:1:2, then hexane is added, the resulting suspension is filtered and dried at room temperature.