RU2599841C1 - Method of aminoglycoside antibiotics in sodium alginate nano-capsules producing - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to nanotechnology and medicine. Described is method of aminoglycoside antibiotics in sodium alginate envelope nano-capsules producing. According to method according to invention aminoglycoside antibiotic is added in portions into sodium alginate suspension in benzene, containing E472c preparation as surfactant with mass ratio of aminoglycoside antibiotic: sodium alginate of 1:1 or 1:3. Mixture is stirred, then methyl ethyl ketone is added. Obtained suspension of nano-capsules is filtered, washed with methyl ethyl ketone and dried. Process is performed within 15 minutes.

EFFECT: method according to invention provides simplification and acceleration of nano-capsules producing process in sodium alginate and increases mass output.

1 cl, 1 dwg, 7 ex

Description

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

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

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. RF 2095055, IPC A61K 9/52, A61K 9/16, A61K 9/10, 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 -15 to -50 ° C, and the separation of 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. RF 2076765, IPC B01D 9/02, published 04/10/1997, 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. RF 2159037, IPC A01N 25/28, A01N 25/30, published on 11/20/2000, a method for producing microcapsules by a polymerization reaction at the interface, containing solid agrochemical material 0.1-55 wt. % suspended in a water-miscible 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 the article “Development of microencapsulated and gel-like products and materials for various industries”, Russian Chemical Journal, 2001, vol. XLV, No. 5-6, p. 125-135 A method for producing microcapsules of drugs by gas-phase polymerization is described, since the authors of the article consider the method of chemical coacervation from aqueous media to be microencapsulated as unsuitable because most of them are water-soluble. The microencapsulation process using the gas phase polymerization method using n-xylylene includes the following main stages: evaporation of the n-xylylene dimer (170 ° C), its thermal decomposition in a pyrolysis furnace (650 ° C at a residual pressure of 0.5 mm Hg), transfer of reaction products to the “cold” polymerization chamber (20 ° C, residual pressure 0.1 mm Hg), precipitation and polymerization on the surface of the protected object. The polymerization chamber is made in the form of a rotating drum, the optimum speed for coating the powder is 30 rpm. The thickness of the shell is regulated by the time of coating. This method is suitable for encapsulation of any solids (with the exception of prone to intense sublimation). The resulting poly-n-xylylene highly crystalline polymer, characterized by high orientation and tight packaging, provides a conformal coating.

The disadvantages of the proposed method are the complexity and duration of the process, the use of gas phase polymerization, which makes the method inapplicable for producing microcapsules of drugs in polymers of protein nature due to denaturation of proteins at high temperatures.

In US Pat. RF 2173140, IPC A61K 009/50, A61K 009/127, published September 10, 2001. A method for producing silicon organolipid microcapsules using a rotary-cavitation installation 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. RF 2359662, IPC A61K 009/56, A61J 003/07, B01J 013/02, A23L 001/00, published 06/27/2009 a method for producing microcapsules using spray cooling in a Niro spray cooling tower under the following conditions: inlet air temperature 10 ° C, outlet air temperature 28 ° C, the rotation speed of the spray drum 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 / 2009/148058 JP, IPC B01J 13/04, A23L 1/00, A61K 35/20, A61K 45/00, A61K 47/08), A61K 47/26, A61K 47/32, A61K 47/34, A61K 47/36, A61K 9/50, B01J 2/04, B01J 2/06, published 12/10/2009 describes a process for producing microcapsules applicable for industrial production in which there is a high content of hydrophilic biologically active substance enclosed in a shell. The proposed microcapsules can be used in food, pharmaceutical and other industries. In the manufacturing process, dispersing compositions are used consisting of hydrophilic biologically active substances and surfactants in solid fat. The temperature is not lower than the melting point of solid fat.

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

In US Pat. WO / 2010/076360 ES, IPC B01J 13/00; A61K 9/14; A61K 9/10; A61K 9/12, published July 8, 2010. A new method is proposed 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, and hence the low yield of the final product.

In US Pat. WO / 2010/014011 NL, IPC A61K 9/50; B01J 13/02; A61K 9/50; B01J 13/02, published February 4, 2010 describes a method for producing microcapsules with a diameter of 0.1 μm to 25 μm, including: a core of a particle with a diameter of 90 nm to 23 μm containing at least 3% of the active component by weight of the particle; a coating that completely covers the main particles containing at least 20% by weight of a hydrophobic polymer selected from cellulose ethers, cellulose esters, shellac, gluten, polylactide, hydrophobic starch derivatives, polyvinyl acetate, acrylic ester polymers or copolymers and / or methacrylic acid ester and combinations thereof. The active component is not released when introduced into aqueous foods, drinks, food or pharmaceutical compositions. After oral administration, however, the active component is released rapidly.

The disadvantages of this method are the complexity, duration of the process, as well as the use of ultrasound and special equipment, the use of acrylic or methacrylic acid copolymers as microcapsule shells that can cause cancerous tumors.

In US Pat. WO / 2011/003805 EP, IPC B01J 13/18; B65D 83/14; C08G 18/00, published January 13, 2011 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. US20110223314, 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 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. US WO / 2011/150138, IPC C11D 3/37; B01J 3/08; C11D 17/00, published December 1, 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. US WO / 2011/127030, 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. US WO / 2011/056935, IPC C11D 17/00; A61K 8/11; B01J 13/02; C11D 3/50, published 05/12/2011 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 benefits that will be received. 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.

In US Pat. WO / 2011/161229 EP, IPC A61K 8/11; B01J 13/14; B01J 3/16; C11D 3/50, published December 29, 2011 describes a method for producing microcapsules containing a polyurea and perfume shell in oil, where the shell is obtained by the reaction of two structurally different diisocyanates in the form of an emulsion. In the process of obtaining microcapsules, protective colloids are used. During the reaction of isocyanates and amines, a protective colloid must be present. This is preferably polyvinylpyrrolidone (PVP). Protective colloid - a polymer system that, in suspension or dispersion, prevents adhesion (agglomeration, coagulation, flocculation). With this method, it can be used for perfumes and all kinds of consumer goods. An exhaustive list of consumer goods cannot be listed. Illustrative examples of consumer products include all applications, including liquid detergents and powder detergents; all personal care and hair care applications, including shampoos, conditioners, comb creams, styling creams, soaps, body creams, etc .; deodorants and antiperspirants.

The disadvantages of this method of obtaining microcapsules are the complexity and duration of the process, the use as a shell of microcapsules of diisocyanates, which are obtained as a result of the reaction of two isocyanates.

In US Pat. WO / 2012/007438 EP, IPC A61K 8/11; A61Q 13/00; B01J 3/16; B01J 3/18, published January 19, 2012 describes a method for producing particles with an average diameter of less than 50 microns, consisting of at least one shell, by the method of stepwise polymerization with the participation of isocyanate monomer. At least one shell is formed by a chain reaction of growth polymerization (preferably free radical polymerization), which is not associated with an isocyanate. The invention also relates to a method for producing such particles in which a shell is formed prior to chain growth of polymerization at a temperature at which a chain reaction of growth is suppressed. The invention also provides fully formulated products, preferably liquids and gels, which contain these particles.

The disadvantages of the proposed method are the complexity and duration of the process, obtaining microcapsules by the chemical method of stepwise polymerization. The particles obtained by this method have a sufficiently large size — 50 μm.

The closest method is the method proposed in US Pat. RF 2134967, IPC A01N 53/00, A01N 25/28, published on 08.27.1999 (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 nanocapsules of water-soluble aminoglycoside antibiotics in sodium alginate, reduce losses in the production of nanocapsules (increase in yield by mass).

The solution of the technical problem is achieved by the method of producing nanocapsules of aminoglycoside antibiotics, characterized in that sodium alginate is used as the shell of the nanocapsules, as well as the preparation of nanocapsules by the physicochemical precipitation method with a non-solvent using a precipitator - methyl ethyl ketone.

The result of the proposed method is to obtain nanocapsules of aminoglycoside antibiotics in sodium alginate for 15 minutes. The yield of nanocapsules is 100%.

EXAMPLE 1. Obtaining nanocapsules of kanamycin in the ratio of core: shell 1: 3

To 1.5 g of sodium alginate in benzene, add 0.01 g of the preparation E472c (glycerol ester with one or two molecules of food fatty acids and one or two molecules of citric acid, moreover, citric acid, as tribasic, can be esterified with other glycerides and as oxoacid with other fatty acids. Free acid groups can be neutralized with sodium) as a surfactant. The resulting mixture is placed on a magnetic stirrer and include stirring. 0.5 g of kanamycin powder is added in small portions to a suspension of sodium alginate in benzene. After the formation of an independent solid phase, 5 ml of methyl ethyl ketone are slowly added. The resulting suspension of nanocapsules is filtered off on a filter, washed with methyl ethyl ketone and dried.

Received 2 g of a white powder. The yield was 100%.

EXAMPLE 2. Obtaining nanocapsules of kanamycin in the ratio of core: shell 1: 1

To 0.5 g of sodium alginate in benzene add 0.01 g of the preparation E472c as a surfactant. The resulting mixture is placed on a magnetic stirrer and include stirring. 0.5 g of kanamycin powder is added in small portions to a suspension of sodium alginate in benzene. After the formation of an independent solid phase, 5 ml of methyl ethyl ketone are slowly added. The resulting suspension of nanocapsules is filtered off, washed with methyl ethyl ketone and dried.

Received 1 g of a white powder. The yield was 100%.

EXAMPLE 3. Obtaining nanocapsules of amikacin in the ratio of core: shell 1: 1

To 0.5 g of sodium alginate in benzene add 0.01 g of the preparation E472c as a surfactant. The resulting mixture is placed on a magnetic stirrer and include stirring. 0.5 g of amikacin powder is added in small portions to a suspension of sodium alginate in benzene. After the formation of an independent solid phase, 5 ml of methyl ethyl ketone are slowly added. The resulting suspension of nanocapsules is filtered off, washed with methyl ethyl ketone and dried.

Received 1 g of a white powder. The yield was 100%.

EXAMPLE 4. Obtaining nanocapsules of amikacin in the ratio of core: shell 1: 3

To 1.5 g of sodium alginate in benzene add 0.01 g of the preparation E472c as a surfactant. The resulting mixture is placed on a magnetic stirrer and include stirring. 0.5 g of amikacin powder is added in small portions to a suspension of sodium alginate in benzene. After the formation of an independent solid phase, 5 ml of methyl ethyl ketone are slowly added. The resulting suspension of nanocapsules is filtered off, washed with methyl ethyl ketone and dried.

Received 2 g of a white powder. The yield was 100%.

EXAMPLE 5. Obtaining nanocapsules of gentamicin sulfate in the ratio of core: shell 1: 1

To 1.5 g of sodium alginate in benzene add 0.01 g of the preparation E472c as a surfactant. The resulting mixture is placed on a magnetic stirrer and include stirring. 1.5 g of gentamicin sulfate powder is added in small portions to a suspension of sodium alginate in benzene. After the formation of an independent solid phase, 5 ml of methyl ethyl ketone are slowly added. The resulting suspension of nanocapsules is filtered off, washed with methyl ethyl ketone and dried.

Received 3 g of a white powder. The yield was 100%.

EXAMPLE 6. Obtaining nanocapsules of gentamicin sulfate in the ratio of core: shell 1: 3

To 1.5 g of sodium alginate in benzene add 0.01 g of the preparation E472c as a surfactant. The resulting mixture is placed on a magnetic stirrer and include stirring. 0.5 g of gentamicin sulfate powder is added in small portions to a suspension of sodium alginate in benzene. After the formation of an independent solid phase, 5 ml of methyl ethyl ketone are slowly added. The resulting suspension of nanocapsules is filtered off, washed with methyl ethyl ketone and dried.

Received 2 g of a white powder. The yield was 100%.

EXAMPLE 7. Determination of the size of nanocapsules by the NTA method.

The measurements were carried out on a Nanosight LM0 multiparameter nanoparticle analyzer manufactured by Nanosight Ltd (Great Britain) in the HS-BF configuration (Andor Luca high-sensitivity video camera, 405 nm semiconductor laser with a power of 45 mW). The device is based on the method of analysis of trajectories of nanoparticles (Nanoparticle Tracking Analysis, NTA), described in ASTM E2834.

The optimal dilution for dilution was 1: 100. The device parameters were selected for measurement: Camera Level = 16, Detection Threshold = 10 (multi), Min Track Length: Auto, Min Expected Size: Auto., Duration of a single measurement 215s, use of a syringe pump.

Claims (1)

A method for producing nanocapsules of an aminoglycoside antibiotic in a shell of sodium alginate, characterized in that sodium alginate is used as the shell of the nanocapsules, while the aminoglycoside antibiotic is added in portions to a suspension of sodium alginate in benzene containing E472c as a surfactant in a weight ratio of aminoglycoside antibiotic : sodium alginate 1: 1 or 1: 3, the mixture is stirred, then methyl ethyl ketone is added, the resulting suspension of nanocapsules is filtered off, washed with m tiletilketonom and dried, the process is carried out for 15 minutes.

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