RU2563618C2 - Method of obtaining microcapsules of biopag-d in pectin - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to the pharmaceutical industry, in particular to a method of obtaining microcapsules of a veterinary preparation biopag-D. The method of obtaining microcapsules of the veterinary preparation biopag-D consists in the fact that as the coating for the microcapsules used is low-esterified or highly-esterified apple or citrus pectin, with the addition of E472c as the surface-active substance to a certain quantity of the suspension of low-esterified or highly-esterified apple or citrus pectin in ethanol, after that the obtained mixture is mixed on a magnetic mixer, with the further addition of the suspension of biopag-D in dimethylsulphoxide, with the following addition of a certain quantity of toluene and water, then the obtained suspension of the microcapsules is filtered, washed with toluene and dried in the dessicator above calcium chloride.

EFFECT: method provides the simplification and acceleration of the process of obtaining the microcapsules of the water-soluble biopag-D.

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Description

The invention relates to the field of microencapsulation of veterinary drugs by the example of Biopag-D in apple and citrus pectin (high and low etherification) by the physicochemical method.

Previously known methods for producing microcapsules of drugs. So, in US 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 November 10, 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 disadvantages of the method are the use of a ball mill and the duration of the process.

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, possibly a portion of the solvent is evaporated, a redispersing agent is added the agent and the mixture are freeze dried. The freeze-dried mixture is then redispersed in an aqueous carrier to separate the microcapsules from organic residues, 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 on 11/20/2000, 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.

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 disadvantage of this method is the use of special equipment - a rotary-quittance installation, which has an ultrasonic effect, which affects the formation of microcapsules and can cause adverse reactions due to the fact that ultrasound destructively affects polymers of a protein nature, therefore, the proposed method is applicable when work with polymers of synthetic origin.

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. WO / 2010/076360 ES, IPC B01J 13/00; A61K 9/14; A61K 9/10; A61K 9/12, published July 8, 2010, proposes a new method for producing solid micro- and nanoparticles with a homogeneous structure with a particle size of less than 10 μm, where the treated solid compounds have a natural crystalline, amorphous, polymorphic and other states associated with the starting compound. The method allows to obtain solid micro- and nanoparticles with substantially spheroidal morphology.

The disadvantage of the proposed method is the complexity of the process, which leads to capsules with a floating output.

In US Pat. WO / 2010/119041 EP, IPC A23L 1/00, published October 21, 2010, a method for producing beads containing an active ingredient encapsulated in a gel matrix of whey protein including denatured protein, serum and active components is proposed. The invention relates to a method for producing beads that contain components such as probiotic bacteria. A method for producing microspheres includes the stage of production of microspheres in accordance with the method of the invention, and the subsequent curing of the microspheres in a solution of an anionic polysaccharide with a pH of 4.6 or lower for at least 10, 30, 60, 90, 120, 180 minutes. Examples of suitable anionic polysaccharides: pectins, alginates, carrageenans. Ideally, whey protein is heat-denaturing, although other denaturation methods are also applicable, for example, pressure-induced denaturation. In a preferred embodiment, whey protein is denatured at a temperature of from 75 ° C to 80 ° C appropriately for from 30 minutes to 50 minutes. As a rule, whey protein is mixed with heat denaturation. Accordingly, the concentration of whey protein is from 5 to 15%, preferably from 7 to 12%, and ideally from 9 to 11% (weight / volume). Typically, the process is carried out by filtration through multiple filters with a gradual reduction in pore size. Ideally, a fine filter has submicron pore sizes, for example from 0.1 to 0.9 microns. The preferred method for producing beads is a method using vibratory encapsulators (Inotech, Switzerland) and machines manufactured by Nisco Engineering AG. As a rule, nozzles have openings of 100 and 600 microns, and ideally about 150 microns.

The disadvantage of this method is the use of special equipment (vibration encapsulators (Inotech, Switzerland)), the production of microcapsules by protein denaturation, the difficulty of isolating the microcapsules obtained by this method - filtering using many filters, which makes the process long.

In US Pat. WO / 2011/003805 EP, IPC B01J 13/18; B65D 83/14; C08G 18/00 describes a method for producing microcapsules that are suitable for use in formulations of sealants, foams, coatings or adhesives.

The disadvantage of the proposed method is the use of centrifugation to separate from the process fluid, the duration of the process, as well as the use of this method not in the pharmaceutical industry.

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, belonging 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 microcapsules of solid 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 October 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 01.09.2011, 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 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 13/02; 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 core material and materials in the environment in which the agent is encapsulated to provide 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 a water-soluble biopag in pectin, to reduce losses upon receipt of microcapsules (increase in yield by mass).

The solution to the technical problem is achieved by the method of producing microcapsules of Biopag-D, characterized in that high-esterified and low-esterified apple or citrus pectins are used as the shell of the microcapsules, as well as the production of microcapsules by the physicochemical precipitation method with a non-solvent using two precipitants - ethanol and toluene, the production process is carried out without special equipment.

A distinctive feature of the proposed method is the use of biopag-D microcapsules and pectins as a shell, as well as the production of microcapsules by the physicochemical precipitation method with a non-solvent using two precipitants - carbinol and toluene.

The result of the proposed method is to obtain microcapsules of Biopag-D in pectins at 25 ° C for 15 minutes. The output of microcapsules is more than 90%.

EXAMPLE 1 Obtaining microcapsules of Biopag-D in apple low esterified pectin, ratio 1: 3

To 3 g of a suspension of low esterified pectin in ethanol, 0.01 g of E472c preparation is added as a surfactant. The resulting mixture is placed on a magnetic stirrer and include stirring. 1 g of a suspension of biopag-D in dimethyl sulfoxide is added to a suspension of pectin in ethanol. Then add 5 ml of toluene and 1 ml of water. The resulting suspension of microcapsules is filtered on a 16-class pore filter, washed with toluene, dried in a desiccator over calcium chloride.

Received 3.8 g of a white powder. The yield was 95%.

EXAMPLE 2 Obtaining microcapsules of Biopag-D in apple highly esterified pectin, the ratio of 1: 3

To 3 g of a suspension of highly esterified pectin in ethanol is added 0.01 g of the preparation E472c as a surfactant. The resulting mixture is placed on a magnetic stirrer and include stirring. 1 g of a suspension of biopag-D powder in 1 ml of dimethyl sulfoxide is transferred to a suspension of pectin in ethanol. Then add 3 ml of toluene, and then 1 ml of distilled water. The resulting suspension of microcapsules is filtered on a 16-class pore filter, washed with toluene, dried in a desiccator over calcium chloride.

Received 3.85 g of a white with cream tint powder. The yield was 96.25%.

EXAMPLE 3 Obtaining microcapsules of Biopag-D in citrus low esterified pectin, ratio 1: 3

To 3 g of a suspension of low esterified pectin in ethanol, 0.01 g of E472c preparation is added as a surfactant. The resulting mixture is placed on a magnetic stirrer and include stirring. 1 g of a suspension of biopag-D in dimethyl sulfoxide is added to a suspension of pectin in ethanol. Then add 5 ml of toluene and 1 ml of water. The resulting suspension of microcapsules is filtered on a 16-class pore filter, washed with toluene, dried in a desiccator over calcium chloride.

Received 3.8 g of a white powder. The yield was 95%.

EXAMPLE 4 Obtaining microcapsules of biopag-D in citrus high esterified pectin, the ratio of 1: 3

To 3 g of a suspension of highly esterified pectin in ethanol is added 0.01 g of the preparation E472c as a surfactant. The resulting mixture is placed on a magnetic stirrer and include stirring. 1 g of a suspension of biopag-D powder in 1 ml of dimethyl sulfoxide is transferred to a suspension of pectin in ethanol. Then add 3 ml of toluene, and then 1 ml of distilled water. The resulting suspension of microcapsules is filtered on a 16-class pore filter, washed with toluene, dried in a desiccator over calcium chloride.

Received 3.85 g of a white with cream tint powder. The yield was 96.25%.

Microcapsules of a veterinary preparation were obtained using Biopag-D as an example in apple or citrus pectin by the physicochemical method of precipitation with a non-solvent using toluene and ethanol as non-solvents. The process is simple to execute and lasts for 15 minutes.

Pectins (E440) are widely used in the production of confectionery jelly and pastel products, for the stabilization of dairy products, in the production of preserves, as well as in bakery and flour confectionery. There is evidence of the use of pectins as stabilizers for the consistency of creams, lotions, shampoos.

The proposed methodology is suitable for the veterinary industry due to minimal losses, speed, ease of preparation and isolation of microcapsules of Biopag-D in apple or citrus pectin.

Claims (1)

A method of producing microcapsules of the veterinary preparation Biopag-D, characterized in that low-esterified or highly esterified apple or citrus pectin is used as the shell of the microcapsules, while to a 3 g suspension of low-esterified or highly esterified apple or citrus pectin in ethanol, add 4 g -active substance, then the resulting mixture is stirred on a magnetic stirrer, after which 1 g of a suspension of biopag-D in dimethyl sulfoxide is added, then add 5 ml of toluene in the case of using low esterified pectin or 3 ml of toluene in the case of using high esterified pectin and 1 ml of water, then the resulting suspension of microcapsules is filtered off, washed with toluene and dried in a desiccator over calcium chloride.