RU2627580C2 - Method of obtaining nanocapules of antibiotics of tetracyclin row in konjac gum - Google Patents

Abstract

FIELD: nanotechnology.

SUBSTANCE: antibiotics are selected from tetracycline, dioxycycline, minocycline, when the method is applied to a suspension of konjac gum in butanol and 0.01 g of E472c preparation as a surfactant, an antibiotic powder is added, then petroleum ether is added dropwise, which is used as a precipitant. The ratio of the amounts of antibiotic to the amount of konjac gum is 1:1, 1:3, 1:5 or 5:1, the resulting suspension of nanocapsules is filtered off and dried.

EFFECT: nanocapsules production process simplification and acceleration, reduction of losses during the nanocapsules production.

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Description

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

Previously known methods for producing microcapsules of drugs. So, in US Pat. 2092155 IPC A61K 047/02, A61K 009/16, publ. 10/10/1997. The Russian Federation has proposed a method of 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. 2095055 IPC A61K 9/52, A61K 9/16, A61K 9/10. Russian Federation, publ. 11/10/1997 a method for producing non-porous solid microspheres is proposed, which involves melting a pharmaceutically inactive carrier substance, dispersing a pharmaceutically active substance in a melt in an inert atmosphere, spraying the resulting dispersion in the form of a fog in a freezing chamber under pressure, in an inert atmosphere, at a temperature 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. 2076765 IPC B01D 9/02. Russian Federation, publ. 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, by changing the temperature, dispersed particles are obtained.

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, A61K31 / 19. Russian Federation, publ. 01/10/1998 a chewing mask of a taste-masked drug with the properties of controlled release of the drug is proposed that contains microcapsules 100-800 μm in diameter and consists of a pharmaceutical core with crystalline ibuprofen and a polymer coating that includes a plasticizer that is 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 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 by gas phase polymerization 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 value of the aqueous phase was decisive in obtaining durable microcapsules with high yield.

The disadvantage of the proposed method for producing microcapsules is the complexity of the process, and hence the floating output of the target capsules.

In US Pat. 2359662 IPC A61K 009/56, A61J 003/07, B01J 013/02, A23L 001/00, publ. 06/27/2009, Russian Federation, a method for producing microcapsules using spray cooling in a Niro spray cooling tower is proposed 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 / 2010/076360 ES IPC B01J 13/00; A61K 9/14; A61K 9/10; A61K 9/12, publ. 07/08/2010 a new method for producing solid micro- and nanoparticles with a homogeneous structure with a particle size of less than 10 microns, where the treated solid compounds have a natural crystalline, amorphous, polymorphic and other conditions associated with the starting compound, is proposed. The method allows to obtain solid micro- and nanoparticles with substantially spheroidal morphology.

The disadvantage of the proposed method is the complexity and duration of the process.

In US Pat. WO / 2010/119041 EP IPC A23L 1/00, publ. October 21, 2010, a method for producing beads containing an active component 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, the 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). As a rule, the product is subject to filtration, which is carried out through many filters with a gradual decrease in pore size. Ideally, a fine filter has a submicron pore size of, 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 is filtration using multiple filters, which makes the process long.

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 / 2011/160733 EP IPC B01J 13/16, publ. 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 microcapsules are formed.

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, publ. 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 producing nanocapsules of tetracycline antibiotics in sodium alginate, reducing losses in obtaining nanocapsules (increase in yield by mass).

The solution of the technical problem is achieved by the method of producing nanocapsules of tetracycline antibiotics, characterized in that konjac gum is used as the shell of the nanocapsules, as well as the preparation of nanocapsules by the physicochemical method of precipitation with a non-solvent using a precipitator - petroleum ether.

A distinctive feature of the proposed method is the use as a shell of nanocapsules of antibiotics of the tetracyclic series of konjac gum, as well as the preparation of nanocapsules by the physicochemical method of precipitation with a non-solvent using a precipitating agent - petroleum ether.

The result of the proposed method is the production of tetracyclic antibiotic nanocapsules in konjac gum at 25 ° C for 15 minutes. The yield of nanocapsules is 100%.

EXAMPLE 1. Obtaining nanocapsules of tetracycline in konjac gum, the ratio of core: shell 1: 3

To a suspension of 0.6 g of konjac gum in butanol and 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 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, 0.2 g of tetracycline powder is added in small portions. Then 5 ml of petroleum ether are added dropwise. The resulting suspension of nanocapsules is filtered and dried.

Obtained 0.8 g of a white powder. The yield was 100%.

EXAMPLE 2. Obtaining nanocapsules of tetracycline in sodium alginate, the ratio of core: shell 1: 1

0.5 g of tetracycline powder is added to a suspension of 0.5 g of konjac gum in butanol and 0.01 g of the drug as a surfactant. Then 5 ml of petroleum ether are added dropwise. The resulting suspension of nanocapsules is filtered and dried.

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

EXAMPLE 3. Obtaining nanocapsules of tetracycline in konjac gum, the ratio of core: shell 1: 5

0.3 g of tetracycline powder is added to a suspension of 1.5 g of konjac gum in butanol and 0.01 g of the preparation E472c as a surfactant. Then 5 ml of petroleum ether are added dropwise. The resulting suspension of nanocapsules is filtered and dried.

Received 1.8 g of a white powder. The yield was 100%.

EXAMPLE 4. Obtaining nanocapsules of tetracycline in konjac comedy, the ratio of the core: shell 5: 1

In a suspension of 0.1 g of konjac gum in butanol and 0.01 g of the preparation E472c, 0.5 g of tetracycline powder is added as a surfactant. Then 5 ml of petroleum ether are added dropwise. The resulting suspension of nanocapsules is filtered and dried.

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

EXAMPLE 5. Obtaining nanocapsules of dioxicycline in konjac gum, the ratio of core: shell 1: 3

To a suspension of 1.5 g of konjac gum in butanol and 0.01 g of the preparation E472c as a surfactant, 0.5 g of dioxicycline powder is added. Then 5 ml of petroleum ether are added dropwise. The resulting suspension of nanocapsules is filtered and dried.

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

EXAMPLE 6. Obtaining nanocapsules of dioxicycline in konjac gum, the ratio of the core: shell 1: 1

0.5 g of dioxicycline powder is added to a suspension of 0.5 g of konjac gum in butanol and 0.01 g of the preparation E472c as a surfactant. Then 5 ml of petroleum ether are added dropwise. The resulting suspension of nanocapsules is filtered and dried.

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

EXAMPLE 7. Preparation of dioxocycline nanocapsules in konjac gum, core: shell ratio 1: 5

0.3 g of dioxicycline powder is added to a suspension of 1.5 g of konjac gum in butanol and 0.01 g of the preparation E472c as a surfactant. Then 5 ml of petroleum ether are added dropwise. The resulting suspension of nanocapsules is filtered and dried.

Received 1.8 g of powder. The yield was 100%.

EXAMPLE 8. Obtaining nanocapsules of dioxicycline in konjac gum, the ratio of the core: shell 5: 1

To a suspension of 0.2 g of konjac gum in butanol and 0.01 g of the preparation E472c, 1.0 g of dioxicycline powder is added as a surfactant. Then 5 ml of petroleum ether are added dropwise. The resulting suspension of nanocapsules is filtered and dried.

Received 1.2 g of powder. The yield was 100%.

EXAMPLE 8. Obtaining nanocapsules of minocycline in konjac gum, the ratio of core: shell 1: 3

0.5 g of minocycline powder is added to a suspension of 1.5 g of konjac gum in butanol and 0.01 g of the preparation E472c as a surfactant. Then 5 ml of petroleum ether are added dropwise. The resulting suspension of nanocapsules is filtered and dried.

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

EXAMPLE 9. Obtaining nanocapsules of minocycline in konjac gum, the ratio of the core: shell 1: 1

0.5 g of minocycline powder is added to a suspension of 0.5 g of konjac gum in butanol and 0.01 g of the preparation E472c as a surfactant. Then 5 ml of petroleum ether are added dropwise. The resulting suspension of nanocapsules is filtered and dried.

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

EXAMPLE 10. Determination of the size of nanocapsules by NTA

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. The duration of a single measurement is 215s, the use of a syringe pump.

Nanocapsules of antibiotics in konjac gum were obtained by the physicochemical method of precipitation with a non-solvent using petroleum ether as a non-solvent. The process is simple to execute and lasts for 15 minutes.

The proposed technique is suitable for the pharmaceutical industry due to minimal losses, speed, ease of preparation and isolation of antibiotic nanocapsules in konjac gum.

Claims (1)

A method for producing nanocapsules of tetracycline antibiotics selected from tetracycline, dioxicycline, minocycline, characterized in that antibiotic powder is added to a suspension of konjac gum in butanol and 0.01 g of the preparation E472c, then petroleum ether is added dropwise, and moreover, petroleum ether is added dropwise the ratio of antibiotics to konjac gum is 1: 1, 1: 3, 1: 5 or 5: 1, the resulting suspension of nanocapsules is filtered and dried.

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