RU2607654C2 - Method of producing nanocapsules of adenine in carrageenan - Google Patents

Abstract

FIELD: nanotechnology.

SUBSTANCE: invention relates to a method of producing nanocapsules of adenine. Specified method is characterized by that carrageenan in benzene is added with glycerol ester with one or two molecules of edible fatty acids and one or two molecules of citric acid as a surfactant, the produced mixture is stirred, added with adenine powder, after formation of an independent solid phase is slowly added with petroleum ether, the produced suspension of nanocapsules is filtered, washed with petroleum ether and dried, herewith the ratio of nucleus/shell in the nanocapsules makes 1:3, 1:1 or 5:1.

EFFECT: invention provides faster and easier process of nanoencapsulation of adenine, as well as higher mass output.

1 cl, 1 dwg, 4 ex

Description

The invention relates to the field of nanotechnology, in particular to crop production.

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 the separation of the obtained 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. 2101010 IPC A61K 9/52, A61K 9/50, A61K 9/22, A61K 9/20, A61K 31/19, Russian Federation, published January 10, 1998, a chewing form of the drug with a taste mask is proposed, which has the properties of a controlled release of the drug contains microcapsules with a size of 100-800 microns in diameter and consists of a pharmaceutical core with crystalline ibuprofen and a polymer coating comprising 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; complexity of execution; the duration of the process.

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 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), deposition 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 the article “Development of Micro- and Nanosystems for the Delivery of Medicines”, Russian Chemical Journal, 2008, vol. LII, No. 1, p. 48-57, a method for producing microcapsules with incorporated proteins is presented, which does not significantly reduce their biological activity, carried out by the process of interfacial crosslinking of soluble starch or hydroxyethyl starch and bovine serum albumin (BSA) using terephthaloyl chloride. The proteinase inhibitor aprotinin, either native or with a protected active center, was microencapsulated when it was introduced into the aqueous phase. The flattened form of lyophilized particles indicates the preparation of microcapsules or particles of a reservoir type. Thus prepared microcapsules were not damaged after lyophilization and easily restored their spherical shape after rehydration in a buffer medium. The pH of the aqueous phase was decisive in the preparation of durable microcapsules in high yield.

The disadvantage of the proposed method for producing microcapsules is the complexity of the process, which, in turn, leads to a decrease in the output of the final capsules.

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 cavitation unit, 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: inlet air temperature 10 ° C, outlet air temperature 28 ° C, spray drum rotation speed of 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 December 10, 2009, describes a process for producing microcapsules applicable for industrial production in which a high content of hydrophilic biologically active substance is encapsulated. The proposed microcapsules can be used in food, pharmaceutical and other industries. Dispersing compositions consisting of hydrophilic biologically active substances and surfactants in solid fat are used in the manufacturing process. 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, 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 one 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 particle core 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 compositions forming 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 of 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 / 2011/127030 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, and the use of special equipment (filter (Albet, Dassel, Germany), a spray dryer for collecting particles (Spray-4M8 dryer from ProCert, Belgium)).

In US Pat. WO / 2011/160733 EP, IPC B01J 13/16, published December 29, 2011, describes a method for producing microcapsules that contain shells and cores of water-insoluble materials. An aqueous solution of a protective colloid and a solution of a mixture of at least two structurally different bifunctional diisocyanates (A) and (B), insoluble in water, are collected together until an emulsion is formed, then added to a mixture of bifunctional amines and heated to a temperature of at least 60 ° C until formation microcapsules.

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 / 2012/007438 EP, IPC A61K 8/11; A61Q 13/00; B01J 13/16; B01J 13/18, 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. 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 the preparation of nanocapsules of water-soluble preparations in water-soluble polymers.

The technical task is to simplify and accelerate the process of obtaining nanocapsules of water-soluble agricultural preparations of the cytokinin group in carrageenan, reduce losses in obtaining nanocapsules (increase in yield by mass).

The solution to the technical problem is achieved by the method of producing adenine nanocapsules, characterized in that carrageenan is used as the nanocapsule shell, as well as the preparation of nanocapsules by the physicochemical method of precipitation with a non-solvent using a precipitating agent - petroleum ether.

Figure 1 shows the particle size distribution in the sample of adenine nanocapsules in carrageenan, below are the static characteristics of the distributions.

The result of the proposed method is to obtain adenine nanocapsules in carrageenan within 15 minutes. The yield of nanocapsules is more than 90%.

EXAMPLE 1

Obtaining nanocapsules of adenine in the ratio of core: shell 1: 3

To 1.5 g of carrageenan in benzene, add 0.01 g of the preparation E472c (glycerol ester with one to two molecules of food fatty acids and one to two molecules of citric acid, moreover, citric acid, as a tribasic, can be esterified with other glycerides, and, like oxoacid, other fatty acids. Free acid groups can be neutralized with sodium as a surfactant. The resulting mixture is placed on a magnetic stirrer and included stirring. 0.5 g of adenine powder is added in portions to the suspension of arrageenan in benzene. After the formation of an independent solid phase, 5 ml of petroleum ether is added very slowly dropwise.The resulting suspension of nanocapsules is filtered off on a filter, washed with petroleum ether and dried.

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

EXAMPLE 2

Obtaining nanocapsules of adenine in the ratio of core: shell 1: 1

To 0.5 g of carrageenan 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 adenine powder is added in portions to a suspension of carrageenan in benzene. After the formation of an independent solid phase, 5 ml of petroleum ether is added dropwise very slowly. The resulting suspension of nanocapsules is filtered off on a filter, washed with petroleum ether and dried.

Received 0.98 g of a white powder. The yield was 98%.

EXAMPLE 3

Obtaining nanocapsules of adenine in the ratio of core: shell 5: 1

To 0.1 g of carrageenan 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 adenine powder is added in portions to a suspension of carrageenan in benzene. After the formation of an independent solid phase, 3 ml of petroleum ether is added dropwise very slowly. The resulting suspension of nanocapsules is filtered off on a filter, washed with petroleum ether and dried.

Received 0.6 g of a white powder. The yield was 100%.

EXAMPLE 4

Sizing nanocapsules by 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 Nanoparticle Tracking Analysis (NTA) method described in ASTM E2834.

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

Claims (1)

A method of producing adenine nanocapsules, characterized in that glycerol ester is added to carrageenan in benzene with one or two molecules of edible fatty acids and one or two molecules of citric acid as a surfactant, the resulting mixture is mixed, adenine powder is added, after the formation of an independent solid phase slowly add petroleum ether, the resulting suspension of nanocapsules is filtered off, washed with petroleum ether and dried, while the ratio of core / shell in nanocapsules with sets 1: 3, 1: 1 or 5: 1.

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