RU2537236C1 - Method for bioencapsulation - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents a method for preparing drug microcapsules by nonsolvent addition differing by the fact that the drugs represent the preparations of cephalosporin group, and a coating is poludan deposited from an aqueous solution by adding diethyl ester and isopropanol at 25 °C as a nonsolvent.

EFFECT: invention provides simplifying and accelerating the process of microcapsules, reducing the microcapsule loss (higher weight yield).

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Description

The invention relates to the field of bioencapsulation, in particular microencapsulation of drugs of the group of cephalosporins related to β-lactam antibiotics in half-bath by the physicochemical method of precipitation with a non-solvent.

Previously known methods for producing microcapsules. So, in US Pat. RU 2092155, IPC A61K 047/02, A61K 009/16 published on 10.10.1997, a method of microencapsulation of drugs based on the use of special equipment using ultraviolet radiation is 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. RU 2095055, IPC A61K 9/52, A61K 9/16, A61K 9/10, published November 10, 1997, the proposed method for producing solid non-porous microspheres involves 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 and the use of special equipment.

In US Pat. RU 2091071 A61K 35/10, published 09/27/1997, a method for producing the preparation by dispersion in a ball mill to obtain microcapsules is proposed.

The disadvantages of the method are the use of a ball mill and the duration of the process.

In US Pat. RU 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. RU 2101010, IPC A61K 9/52, A61K 9/50, A61K 9/22, A61K 9/20, A61K 31/19, published January 10, 1998, there is proposed a chewing form of the drug with a taste mask that 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, 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; complexity of execution; the duration of the process.

In US Pat. RU 2139046, IPC A61K 9/50, A61K 49/00, A61K 51/00, 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. 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. RU 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, 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. EP WO / 2011/003805, 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.

The closest method is the method proposed in US Pat. RU 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 microcapsules of water-soluble drugs of the cephalosporin group, reduce losses in obtaining microcapsules (increase in yield by mass).

The solution to the technical problem is achieved by the bioencapsulation method, characterized in that half-dan 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 - diethyl ether and isopropanol, the production process is carried out without special equipment.

A distinctive feature of the proposed method is the use of a capsule of microcapsules of drugs of the cephalosporin group belonging to β-lactam antibiotics as a half-donor, as well as the preparation of microcapsules by the physicochemical precipitation with a non-solvent using two precipitants - diethyl ether and isopropanol.

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

EXAMPLE 1. Obtaining microcapsules of cefotaxime in the semidane using diethyl ether and isopropanol as precipitants, the ratio of 3: 1

To 2 g of 1% aqueous half-dan 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, 1 ml of diethyl ether is added dropwise very slowly as the first precipitant, and then 5 ml of isopropanol as the second. The resulting suspension of microcapsules is filtered on a 16-class pore filter, washed with acetone, dried in a desiccator over calcium chloride.

Received 0,077 g of a white powder. The yield was 77%.

EXAMPLE 2. Obtaining microcapsules of ceftriaxone in the semidane using diethyl ether and isopropanol as precipitants, the ratio of 3: 1

To 2 g of 1% aqueous half-dan 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, 1 ml of diethyl ether is added dropwise very slowly as the first precipitant, and then 5 ml of isopropanol as the second. The resulting suspension of microcapsules is filtered on a 16-class pore filter, washed with acetone, dried in a desiccator over calcium chloride.

Received 0,098 g of a white powder. The yield was 98%.

EXAMPLE 3. Obtaining microcapsules of cefazolin in the semidane using diethyl ether and isopropanol as precipitants, the ratio of 3: 1

0.060 g of cefazolin powder and 0.05 g of preparation E472c as a surfactant are added to 2 g of 1% aqueous half-dan. 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, 1 ml of diethyl ether is added dropwise very slowly as the first precipitant, and then 5 ml of isopropanol as the second. The resulting suspension of microcapsules is filtered on a 16-class pore filter, washed with acetone, dried in a desiccator over calcium chloride.

Received 0,096 g of a white powder. The yield was 96%.

Microcapsules of drugs of the cephalosporin group belonging to β-lactam antibiotics were obtained in half-bath by the physicochemical method of precipitation with a non-solvent using diethyl ether and isopropanol as non-solvents. The process is simple to execute and lasts for 15 minutes, does not require special equipment.

Half-Dan is a biosynthetic polyribonucleotide complex of polyadenyl and polyuridyl acids (in equimolar ratios). Inducer of the synthesis of endogenous interferon. It stimulates the formation of mainly alpha interferon, to a lesser extent β and γ interferons. It has a pronounced antiviral and immunomodulatory activity.

The proposed method 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 the half-den.

Claims (1)

A method of producing microcapsules of drugs by the method of precipitation with a non-solvent, characterized in that the drugs used are the group of cephalosporins, as a shell is a semidane, which is precipitated from an aqueous solution by adding diethyl ether and isopropanol as a solvent at 25 ° C.