RU2584226C2 - Method of producing antibiotic nanocapsules in interferon - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: invention relates to encapsulation. Described is a method of producing antibiotic nanocapsules - ceftriaxone or cefotaxime. Envelope used is α- or β-interferon human leukocyte. According to disclosed method antibiotic is added to 1 % aqueous solution of interferon in presence of preparation E472c as a surfactant, with weight ratio of ceftriaxone or cefotaxime and interferon of 3:1, respectively. Mixture is then stirred and hexane is added. Obtained suspension of nanocapsules is filtered, washed and dried. Process of nanoencapsulation is performed at 25 °C for 15 minutes.

EFFECT: invention provides a simpler and faster process of producing nanocapsules, reduces losses during production thereof (high mass output).

1 cl, 1 dwg, 5 ex

Description

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

Previously known methods for producing microcapsules of drugs. So, in Pat. 2092155, IPC A61K 047/02, A61K 009/16, published on 10/10/1997, Russian Federation, a method for microencapsulation of drugs based on the use of special equipment using ultraviolet radiation was 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, including 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 January 10, 1998, a chewing form of the drug with a taste masking having the properties of controlled release of the drug is proposed 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. 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 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, 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 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. 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 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 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 / 2011/104526 GB, IPC B01J 13/00; B01J 13/14; С09В 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, the benefit will be used 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 nanocapsules of water-soluble drugs of the cephalosporin group in the α- and β-forms of human leukocyte interferon, to reduce losses in the production of nanocapsules (increase in mass yield).

The solution of the technical problem is achieved by the method of producing nanocapsules, characterized in that the human leukocyte interferon in α- and β-forms is used as the nanocapsule shell when the nanocapsules are obtained by the physicochemical method of non-solvent precipitation using a precipitant - hexane, the production process is carried out without special equipment.

A distinctive feature of the proposed method is the use as a shell of nanocapsules of drugs of the cephalosporin group belonging to β-lactam antibiotics, human leukocyte interferon in α and β forms when they are obtained by the physicochemical method of precipitation with a non-solvent using hexane as a precipitant.

The result of the proposed method is the production of nanocapsules of drugs of the cephalosporin group related to P-lactam antibiotics in the α- and β-forms of human leukocyte interferon at 25 ° C for 15 minutes. The yield of nanocapsules is 100%.

EXAMPLE 1. Obtaining nanocapsules of cefotaxime in human leukocyte interferon (β-interferon), the ratio of 3: 1

To 2.5 g of a 1% aqueous solution of human leukocyte interferon (β-interferon) add 0.075 g of cefotaxime powder and 0.05 g of the preparation E472c as a surfactant. The resulting mixture is placed on a magnetic stirrer and include stirring. After dissolving the components of the reaction mixture until a clear solution forms, 6 ml of hexane is very slowly added dropwise as a precipitant. The resulting suspension of nanocapsules is filtered on a 16-class Schott filter, washed with hexane, dried in a desiccator over calcium chloride.

Obtained 0.1 g of a white powder. The yield was 100%.

EXAMPLE 2. Obtaining nanocapsules of cefotaxime in interferon human leukocyte (α-interferon), the ratio of 3: 1

To 2 g of a 1% aqueous solution of human leukocyte interferon (α-interferon) add 0.060 g of cefatoxime powder and 0.05 g of the preparation E472c as a surfactant. The resulting mixture is placed on a magnetic stirrer and include stirring. After dissolving the components of the reaction mixture until a clear solution forms, 6 ml of hexane are very slowly added dropwise. The resulting suspension of nanocapsules is filtered on a 16-class Schott filter, washed with hexane, dried in a desiccator over calcium chloride.

Received 0.08 g of a white powder. The yield was 100%.

EXAMPLE 3. Obtaining nanocapsules of ceftriaxone in human leukocyte interferon (β-interferon), the ratio of 3: 1

To 2.5 g of a 1% aqueous solution of human leukocyte interferon (β-interferon) add 0.075 g of ceftriaxone powder and 0.05 g of the preparation E472c as a surfactant. The resulting mixture is placed on a magnetic stirrer and include stirring. After dissolving the components of the reaction mixture until a clear solution forms, 6 ml of hexane are very slowly added dropwise. The resulting suspension of nanocapsules is filtered on a 16-class Schott filter, washed with hexane, dried in a desiccator over calcium chloride.

Obtained 0.1 g of a white powder. The yield was 97%.

NOTE 4: Preparation of ceftriaxone nanocapsules in human leukocyte interferon (α-interferon), 3: 1 ratio

To 2 g of a 1% aqueous solution of human leukocyte interferon (α-interferon) add 0.060 g of ceftriaxone powder and 0.05 g of the preparation E472c as a surfactant. The resulting mixture is placed on a magnetic stirrer and include stirring. After dissolving the components of the reaction mixture until a clear solution forms, 6 ml of hexane are very slowly added dropwise. The resulting suspension of nanocapsules is filtered on a 16-class Schott filter, washed with hexane, dried in a desiccator over calcium chloride.

Received 0.08 g of a white powder. The yield was 100%.

EXAMPLE 5. 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 by bASTM 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.

E472 c is a glycerol ester with one or two molecules of edible fatty acids and one or two molecules of citric acid, moreover, citric acid, as a tribasic acid, can be esterified with other glycerides and as an acid with other fatty acids. Free acid groups can be neutralized with sodium

Nanocapsules of drugs of the cephalosporin group in α- and β-forms of human leukocyte interferon were obtained. The process is simple to execute and lasts for 15 minutes, does not require special equipment.

It should be noted that the preparation of nanocapsules of water-soluble preparations in water-soluble polymers is a particularly difficult task. To solve this problem, it is necessary to select a method for producing microcapsules. For nanocapsulation, the physicochemical method was chosen due to the rapidity and ease of execution.

The proposed technique is suitable for the pharmaceutical industry due to the minimal losses, speed, ease of preparation and isolation of cephalosporin nanocapsules related to β-lactam antibiotics in the α- and β-forms of human leukocyte interferon.

Claims (1)

A method of producing ceftriaxone or cefotaxime nanocapsules, which involves the use of human leukocyte interferon α- or β-interferon as the nanocapsule shell, while ceftriaxone or cefotaxime powder is added to a 1% aqueous solution of interferon in the presence of E472c as a surfactant, at a mass ratio of ceftriaxone or cefotaxime and interferon 3: 1, stirred until a clear solution is formed, hexane is added, the resulting suspension of nanocapsules is filtered off, washed and shat, the process is carried out at 25 ° C for 15 minutes.

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