RU2550950C1 - Method of production of nanocapsules biopag-d - Google Patents

Abstract

FIELD: nanotechnology.

SUBSTANCE: distinctive feature of the proposed method is the use of biopag-D and the microcapsule shells of sodium carboxymethyl cellulose, as well as the use of a precipitator - 1,2-dichloroethane in the preparation of nanocapsules by physico-chemical precipitation method by nonsolvent.

EFFECT: simplifying and speeding up the process of obtaining the microcapsules and increase in the yield by weight.

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Description

The invention relates to the field of nanotechnology and veterinary medicine, in particular to a method for producing nanocapsules of biopag-D sodium carboxymethyl cellulose.

Previously known methods for producing microcapsules of drugs. So, in Pat. 2092155, IPC A61K 047/02, A61K 009/16, published October 10, 1997, Russian Federation, a method for microencapsulation of drugs based on the use of special equipment using ultraviolet radiation is proposed.

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

In US Pat. 2095055, IPC A61K 9/52, A61K 9/16, A61K 9/10, Russian Federation, published 10.11.1997, a method for producing solid non-porous microspheres, includes melting a pharmaceutically inactive carrier substance, dispersing the pharmaceutically active substance in a melt in an inert atmosphere spraying the resulting dispersion in the form of fog in a freezing chamber under pressure in an inert atmosphere at a temperature of from -15 to -50 ° C and separating the resulting microspheres into fractions by size. A suspension intended for administration by parenteral injection contains an effective amount of said microspheres distributed in a pharmaceutically acceptable liquid vector, the pharmaceutically active substance of the microsphere being insoluble in said liquid medium.

The disadvantages of the proposed method: the complexity and duration of the process, the use of special equipment.

In US Pat. 2091071, IPC A61K 35/10, Russian Federation, published 09/27/1997, a method for producing the preparation by dispersion in a ball mill to obtain microcapsules is proposed.

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

In US Pat. 2076765, IPC B01D 9/02, Russian Federation, published April 10, 1997, a method for producing 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 dispersed particles are obtained by changing the temperature.

The disadvantage of this method is the difficulty of execution: obtaining microcapsules by dispersion with subsequent change in temperature, which slows down the process.

In US Pat. 2101010, IPC A61K 9/52, A61K 9/50, A61K 9/22, A61K 9/20, A61K 31/19, Russian Federation, published 01/10/1998, a chewing form of the drug with a taste masking having the properties of a controlled release of the drug The preparation contains microcapsules with a size of 100-800 microns in diameter and consists of a pharmaceutical core with crystalline ibuprofen and a polymer coating, including a plasticizer, flexible enough to withstand chewing. The polymer coating is a methacrylic acid based copolymer.

The disadvantages of the invention: the use of a copolymer based on methacrylic acid, as these polymer coatings can cause cancerous tumors; obtaining microcapsules by suspension polymerization; complexity of execution; the duration of the process.

In US Pat. 2139046, IPC A61K 9/50, A61K 49/00, A61K 51/00, Russian Federation, published on 10/10/1999, a method for producing microcapsules as follows. An oil-in-water emulsion is prepared from an organic solution containing dissolved mono-, di-, triglyceride, preferably tripalmitin or tristearin, and possibly a therapeutically active substance, and an aqueous solution containing a surfactant, optionally a part of the solvent is evaporated, add the redispersing agent and the mixture are freeze dried. After freezing, the mixture is then redispersed in an aqueous carrier to separate the microcapsules from residues of 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 US Pat. 2159037, IPC A01N 25/28, A01N 25/30, Russian Federation, published November 20, 2000, a method for producing microcapsules by a polymerization reaction at the phase boundary, containing solid agrochemical material 0.1-55 wt.% Suspended in a mixture with water organic liquid, 0.01-10 wt.% non-ionic dispersant, active at the phase boundary and not acting as an emulsifier.

The disadvantages of the proposed method: complexity, duration, the use of high shear mixer, obtaining microcapsules by the chemical polymerization method, technological complexity.

In US Pat. 2173140, IPC A61K 009/50, A61K 009/127, Russian Federation, published September 10, 2001. A method for producing silicon organolipid microcapsules using a rotary-cavitation unit with high shear forces and powerful sonar acoustic and ultrasonic dispersion ranges is proposed.

The disadvantages of the proposed method: complexity, duration, the use of high shear mixer.

In US Pat. 2359662, IPC A61K 009/56, A61J 003/07, B01J 013/02, A23L 001/00, published June 27, 2009, Russian Federation, a method for producing microcapsules using spray cooling in a Niro spray cooling tower under the following conditions: air temperature inlet 10 ° C; outlet air temperature 28 ° C; spray drum rotation speed 10,000 rpm. The microcapsules of 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 certain conditions (air temperature at the inlet 10 ° C, air temperature at the outlet 28 ° C, rotation speed of the spray drum 10,000 rpm).

In US Pat. 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 03/10/2011 US describes a method for producing microcapsules by suspension polymerization, which belongs to the group of chemical methods using a new device and ultraviolet radiation.

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

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

The disadvantages of this method are the complexity of execution and the duration of the process.

In US Pat. 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 10/13/2011 several methods for producing microcapsules are proposed: interfacial polymerization, thermally induced phase separation, spray drying, evaporation of the solvent, 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), a spray dryer for collecting particles (Spray-4M8 Dryer from ProCepT, Belgium)).

In US Pat. WO / 2011/104526 GB, IPC B01J 13/00; B01J 13/14; C09B 67/00; C09D 11/02 published September 1, 2011, a method for producing a dispersion of encapsulated solid particles in a liquid medium is proposed, comprising: a) grinding a composition comprising solid, liquid media and polyurethane dispersants with an acid number from 0.55 to 3.5 mmol per gram of dispersant, said composition comprises from 5 to 40 parts of a polyurethane dispersant per 100 parts of solid products, by weight; and b) crosslinking the polyurethane dispersant in the presence of a solid and liquid medium, as for the encapsulation of solid particles, which polyurethane dispersant contains less than 10% by weight of repeating elements from polymer alcohols.

The disadvantages of the proposed method are the complexity and duration of the process for producing microcapsules, as well as the fact that the encapsulated particles of the proposed method are useful as dyes in ink, especially inkjet inks, for the pharmaceutical industry this technique is not applicable.

In US Pat. WO / 2011/056935 US, IPC C11D 17/00; A61K 8/11; B01J 3/02; C11D 3/50 published May 12, 2011 describes a method for producing microcapsules with a size of 15 microns or more. Polymers of the group consisting of polyethylene, polyamides, polystyrenes, polyisoprenes, polycarbonates, polyesters, polyacrylates, polyureas, polyurethanes, polyolefins, polysaccharides, epoxies, vinyl polymers and mixtures thereof are proposed as a shell material. The proposed polymer shells are sufficiently impervious to the core material and materials in the environment in which the agent is encapsulated, the benefit will be used to provide the benefits that will be obtained. The core of encapsulated agents may include perfumes, silicone oils, waxes, hydrocarbons, higher fatty acids, essential oils, lipids, skin cooling fluids, vitamins, sunscreens, antioxidants, glycerin, catalysts, bleaching particles, particles of silicon dioxide, etc.

The disadvantages of the proposed method are the complexity, duration of the process, the use as shells of microcapsules of polymers of synthetic origin and their mixtures.

The closest method is the method proposed in US Pat. 2134967, IPC A01N 53/00, A01N 25/28, published on 08.27.1999, 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 this method is dispersion in an aqueous medium, which makes the proposed method inapplicable for producing microcapsules of water-soluble preparations in water-soluble polymers.

The technical task is to simplify and accelerate the process of obtaining microcapsules of Biopag-D in sodium carboxymethyl cellulose, reduce losses in the production of microcapsules (increase in mass yield).

The solution of the technical problem is achieved by the method of producing nanocapsules of Biopag-D, characterized in that sodium carboxymethyl cellulose is used as the shell of the microcapsules in the preparation of nanocapsules by the physicochemical method of precipitation with a non-solvent using a precipitant - 1,2-dichloroethanol, the production process is carried out without special equipment.

A distinctive feature of the proposed method is the use of sodium carboxymethyl cellulose as a nanocapsule shell when they are obtained by the physicochemical method of non-solvent precipitation using 1,2-dichloroethane as a precipitant.

The result of the proposed method is the preparation of nanocapsules of veterinary drugs using Biopag-D as an example in sodium carboxymethyl cellulose at 25 ° C for 15 minutes. The yield of nanocapsules is more than 90%.

EXAMPLE 1 Obtaining nanocapsules of biopag-D, the ratio of the core: shell 3: 1

To 1 g of sodium carboxymethyl cellulose in isopropanol, 3 g of Biopag-D and 0.05 g of the preparation E472c are slowly added as a surfactant. The resulting mixture is placed on a magnetic stirrer and include stirring. Then add 5 ml of 1,2-dichloroethane. The resulting suspension of nanocapsules is filtered off, washed with 1,2-dichloroethane and dried.

Received 4 g of a white powder.

EXAMPLE 2 Obtaining nanocapsules of biopag-D, the ratio of the core: shell 1: 1

To 1 g of sodium carboxymethyl cellulose in isopropanol is slowly added 1 g of biopag-D and 0.05 g of the preparation E472c as a surfactant. The resulting mixture is placed on a magnetic stirrer and include stirring. Then add 5 ml of 1,2-dichloroethane. The resulting suspension of nanocapsules is filtered off, washed with 1,2-dichloroethane and dried.

Received 2 g of a white powder.

EXAMPLE 3 Obtaining nanocapsules of biopag-D, the ratio of the core: shell 1: 3

To 3 g of sodium carboxymethyl cellulose in isopropanol is slowly added 1 g of biopag-D and 0.05 g of the preparation E472c as a surfactant. The resulting mixture is placed on a magnetic stirrer and include stirring. Then add 5 ml of 1,2-dichloroethane. The resulting suspension of nanocapsules is filtered off, washed with 1,2-dichloroethane and dried.

Received 4 g of a white powder.

Nanocapsules of a veterinary preparation were obtained using the example of Biopag-D in sodium carboxymethyl cellulose. The process is simple to execute and lasts for 15 minutes, does not require special equipment.

The proposed technique is suitable for the veterinary industry due to the minimal losses, speed, ease of preparation and isolation of biopag-D nanocapsules in sodium carboxymethyl cellulose.

Claims (1)

A method for producing biocage-D nanocapsules, characterized in that sodium carboxymethyl cellulose is used as a shell, which is precipitated from isopropanol in the presence of glycerol ester with one or two molecules of food fatty acids and one or two molecules of citric acid as a surfactant by adding 1,2-dichloroethane as a precipitant, and in this case, a suspension of the obtained nanocapsules is dried at 25 ° C.