RU2491939C1 - Method for preparing drug microcapsules of cephalosporin in konjac gum in chloroform - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to microcapsulation of drug preparations of cephalosporins referred to β-lactam antibiotics in konjac gum by physical-chemical precipitation in a non-solvent. Konjac gum is used as a microcapsule membrane. The microcapsules are prepared by physical-chemical precipitation in the non-solvent with using two precipitation agents - carbinol and chloroform. The process of microcapsules is carried out at 25°C with no special equipment required.

EFFECT: method according to the invention provides simplifying and accelerating the process of microcapsules of drug preparations of cephalosporins, and reducing losses (higher weight yield).

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Description

The invention relates to the field of microencapsulation of drugs of the group of cephalosporins related to β-lactam antibiotics in konjac gum by the physicochemical method of precipitation with a non-solvent.

Previously known methods for producing microcapsules of drugs. So, in US Pat. 2092155 IPC A61K 047/02, A61K 009/16 published on 10/10/1997 The Russian Federation 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 published 10.11.1997, a method for producing solid non-porous microspheres is proposed which includes the melting of a pharmaceutically inactive carrier substance, dispersion of a 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. 2076765 IPC B01D 9/02 Russian Federation 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. 2101010 IPC A61K 9/52, A61K 9/50, A61K 9/22, A61K 9/20, A61K 31/19 Russian Federation published 10.01.1998 A chewing form of the drug with a taste mask is proposed, which has the properties of a controlled release of the drug, which 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 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, optionally a portion of the solvent is evaporated, add the redispersing 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 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 an organic liquid mixed with water, 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 describes a method for producing microcapsules of drugs by gas-phase polymerization, since the authors of the article consider the method of chemical coacervation from aqueous media to microencapsulate drugs unsuitable 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.

The article “Development of micro- and nanosystems for drug delivery”, Russian Chemical Journal, 2008, vol. LII, No. 1, pp. 48-57, presents a method for producing microcapsules with incorporated proteins, which does not significantly reduce their biological activity, carried out by the interfacial process crosslinking soluble starch or hydroxyethyl starch and bovine serum albumin (BSA) using terephthaloyl chloride. The proteinase-aprotinin inhibitor, 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, and hence the floating output of the target capsules.

In US Pat. 2173140 IPC A61K 9/50, A61K 9/127 Russian Federation published 09.10.2001 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 9/56, A61J 3/07, B01J 13/02, A23L 1/00 published 06/27/2009 The Russian Federation proposed a method for producing microcapsules using spray cooling in a Niro spray cooling tower under the following conditions: inlet air temperature 10 ° C , the air temperature at the outlet 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 / 2010/076360 ES IPC B01J 13/00; A61K 9/14; A61K 9/10; AK61K 9/12 published July 8, 2010, 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, is proposed. The method allows one 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 published October 21, 2010 provides a method for producing beads containing an active component encapsulated in a gel matrix of whey protein, including denatured protein, serum and active components. The invention relates to a method for producing beads that contain components such as probiotic bacteria. The method of producing microspheres includes the stage of production of microspheres in accordance with the method of the invention, and subsequent curing of the microspheres in a solution of 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, such as 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). Typically, the product is subject to filtration, which is carried out through many 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 is filtration using multiple filters, which makes the process long.

In US Pat. WO / 2011/003805 EP IPC B01J 13/18; B65D 83/14; C08G 18/00 published 01/13/2011 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 2006.01.01. B05D 007/00, B05C 3/02 B05C 003/02; B05C 11/00 B05C 011/00; B05D 1/18; B05D 001/18; B05D 3/02; B05D 003/02; B05D 3/06 B05D 003/06 dated 10.03. 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 December 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 on 10/13/2011 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; С09В 67/00; C09D 11/02 published September 1, 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 of 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, since for the encapsulation of solid particles the 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.

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.

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. 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 water-soluble drugs of the cephalosporin group in konjac gum, to reduce losses in the production of microcapsules (increase in yield by mass).

The solution of the technical problem is achieved by the method of producing microcapsules of drugs of the cephalosporin group related to β-lactam antibiotics, characterized in that konjac gum is used as the shell of the microcapsules, as well as the production of microcapsules by the physicochemical method of precipitation with a non-solvent using two precipitants - carbinol and chloroform, the receipt process is carried out without special equipment.

A distinctive feature of the proposed method is the use as a shell of microcapsules of drugs of the cephalosporin group related to β-lactam antibiotics in konjac gum, as well as the preparation of microcapsules by the physicochemical precipitation method with a non-solvent using two precipitants - carbinol and chloroform.

The result of the proposed method is to obtain microcapsules of drugs of the group of cephalosporins related to β-lactam antibiotics in konjac gum at 25 ° C for 15 minutes. The output of microcapsules is more than 90%.

The konjac gum needed for microencapsulation was manufactured under the trade names konjac cercon and konjac gum 3600.

EXAMPLE 1 Obtaining microcapsules of ceftriaxone in konjac gum 3600 using carbinol and chloroform as precipitants, the ratio of 1: 3

To 6 g of a 5% solution of konjac gum 3600 in chloroform 0.01 g of the preparation E472c as a surfactant. The resulting mixture was placed on a magnetic stirrer and included stirring, 0.1 g of ceftriaxone powder was dissolved in 0.5 ml of water and transferred to a solution of konjac gum 3600 in chloroform. After ceftriaxone formed an independent solid phase, 5 ml of carbinol and 1 ml of distilled water are added very slowly dropwise. The resulting suspension of microcapsules is filtered on a 16-class pore filter, washed with acetone, dried in a desiccator over calcium chloride.

Received 0.396 g of a white powder. The yield was 99%.

EXAMPLE 2 Preparation of ceftriaxone microcapsules in kerocon konjac using carbinol and chloroform as precipitants, 1: 3 ratio

To 6 g of a 5% solution of konjac cerocon in chloroform 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 was placed on a magnetic stirrer and included stirring, 0.1 g of ceftriaxone powder was dissolved in 0.5 ml of water and transferred to a solution of kerzhak cerocon in chloroform. After ceftriaxone formed an independent solid phase, 5 ml of carbinol and 1 ml of distilled water are added very slowly dropwise. The resulting suspension of microcapsules is filtered on a 16-class pore filter, washed with acetone, dried in a desiccator over calcium chloride.

Received 0.396 g of a white powder. The yield was 99%.

EXAMPLE 3 Preparation of cefepime microcapsules in konjac gum 3600 using carbinol and chloroform as precipitants, 1: 3 ratio

To 6 g of a 5% solution of konjac gum 3600 in chloroform 0.01 g of the preparation E472c as a surfactant. The resulting mixture was placed on a magnetic stirrer and included stirring, 0.1 g of cefepime powder was dissolved in 0.5 ml of water and transferred to a solution of konjac gum 3600 in chloroform. After cefepime formed an independent solid phase, 5 ml of carbinol and 1 ml of distilled water are added dropwise very slowly. The resulting suspension of microcapsules is filtered on a 16-class pore filter, washed with acetone, dried in a desiccator over calcium chloride.

Received 0.36 g of a white powder. The yield was 90%.

EXAMPLE 4 Preparation of cefepime microcapsules in kerocon konjac using carbinol and chloroform as precipitants, 1: 3 ratio

To 6 g of a 5% solution of konjac cerocon in chloroform 0.01 g of the preparation E472c as a surfactant. The resulting mixture was placed on a magnetic stirrer and included stirring, 0.1 g of cefepime powder was dissolved in 0.5 ml of water and transferred into a solution of konjac cerocon in chloroform. After cefepime formed an independent solid phase, 5 ml of carbinol and 1 ml of distilled water are added dropwise very slowly. The resulting suspension of microcapsules is filtered on a 16-class pore filter, washed with acetone, dried in a desiccator over calcium chloride.

Received 0.364 g of a white powder. The yield was 91%.

Microcapsules of drugs of the cephalosporin group related to β-lactam antibiotics were obtained in konjac gum by the physicochemical method of precipitation with a non-solvent using carbinol and chloroform as non-solvents. The process is simple to execute and lasts for 15 minutes, does not require special equipment.

Konzhakova gum is widely used in the pharmaceutical industry in drugs for weight loss and stool regulation, as a binder in tablets. In the Russian Federation it is allowed in food products according to the TI in the amount of up to 10 g / kg of the product (paragraph 3.6.23 of SanPiN 2.3.2.1293-03). Technological functions: thickener, gelling agent, stabilizer, tabletting agent. Composition: the neutral polysaccharide glucomannan consists of D-glucose and D-mannose in a ratio of 1: 4 to 2: 3.

The proposed technique is suitable for the pharmaceutical industry due to the minimal losses, speed, ease of preparation and isolation of microcapsules of cephalosporins related to β-lactam antibiotics in konjac gum.

Claims (1)

A method of producing microcapsules of drugs of the cephalosporin group in konjac gum in chloroform, characterized in that konjac gum is used as the shell of the microcapsules, as well as the preparation of microcapsules by the physicochemical method of precipitation with a non-solvent using two precipitants - carbinol and chloroform, the production process is carried out at 25 ° C without special equipment.