RU2619328C2 - Method of producing antibiotic nanocapsules in gellan gum - Google Patents

Abstract

FIELD: pharmaceutics.

SUBSTANCE: invention relates to chemical-pharmaceutical industry and represents a method drug encapsulation by non-solvent addition, characterized by the fast that the cores of nanocapsules are antibiotics, the envelope of them is gellan gum in ratio shell: nucleus 3:1, upon that gellan gum in hexane in the presence of the preparation E472 as a surfactant is complemented with antibiotic powder then butylchloride is added in droplets, obtained suspension of nanocapsules is filtered and dried.

EFFECT: invention allows to simplify and accelerate the process of producing nanocapsules and increase mass output.

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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, published on 10/10/1997, Russian Federation, a method of 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, includes melting a pharmaceutically inactive carrier substance, dispersing the pharmaceutically active substance in a melt in an inert atmosphere spraying the obtained 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. 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, optionally, a therapeutically active substance, and an aqueous solution containing a surfactant, possibly a part 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. 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 p-xylylene includes the following main stages: evaporation of the p-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-p-xylylene is a highly crystalline polymer, characterized by high orientation and tight packing, 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 a determining factor 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. 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-quittance installation, 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: air temperature inlet 10 ° C; outlet air temperature 28 ° C; spray drum rotation speed 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, 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 and duration of the process.

In US Pat. WO / 2010/119041 EP, IPC A23L 1/00, published October 21, 2010, a method for producing beads containing an active component encapsulated in a gel matrix of a 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. 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 - filtering using many filters, which makes the process long.

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, dated March 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 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 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 ProCepT, 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, for the encapsulation of solid particles of which 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 ink, 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 (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 antibiotics in gellan gum, reduce losses in obtaining nanocapsules (increase in yield by mass).

The solution of the technical problem is achieved by the method of producing antibiotic nanocapsules, characterized in that gellan gum is used as the nanocapsule shell, as well as the preparation of nanocapsules by the physicochemical precipitation method with a non-solvent using a precipitant - butyl chloride, the production process is carried out without special equipment.

A distinctive feature of the proposed method is the use of gellan gum antibiotics as a shell of nanocapsules, as well as the preparation of nanocapsules by a physicochemical precipitation method with a non-solvent using a precipitator, butyl chloride.

The result of the proposed method is to obtain antibiotic nanocapsules in gellan gum at 25 ° C for 15 minutes. The yield of nanocapsules is 100%.

EXAMPLE 1. Obtaining nanocapsules of ceftriaxone, the ratio of the core: shell 1: 3

To a suspension of 1.5 g of gellan gum in hexane and 0.01 g of the preparation E472c (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 oxoacid - other fatty acids. Free acid groups can be neutralized with sodium. 0.5 g of ceftriaxone powder is added in small portions as a surfactant. Then 5 ml of butyl chloride are added dropwise. The resulting suspension The nanocapsules are filtered and dried.

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

EXAMPLE 2. Obtaining nanocapsules of cefazolin, the ratio of the core: shell 1: 3

0.5 g of cefazolin powder is added to a suspension of 1.5 g of gellan gum gum in hexane and 0.01 g of the preparation as a surfactant. Then 5 ml of butyl chloride are added dropwise. The resulting suspension of nanocapsules is filtered and dried.

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

EXAMPLE 3. Obtaining nanocapsules of cefepime, the ratio of the core: shell 1: 3

0.5 g of cefepime powder is added to a suspension of 1.5 g of gellan gum gum in hexane and 0.01 g of the preparation E472c as a surfactant. Then 5 ml of butyl chloride are added dropwise. The resulting suspension of nanocapsules is filtered and dried.

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

EXAMPLE 4. Obtaining nanocapsules of cefatoxime, the ratio of core: shell 1: 3

To a suspension of 1.5 g of gellan gum in hexane and 0.01 g of the preparation E472c, 0.5 g of cefatoxime powder is added as a surfactant. Then 5 ml of butyl chloride 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 amikacin, the ratio of core: shell 1: 3 (see Fig. 1)

To a suspension of 1.5 g of gellan gum in hexane and 0.01 g of the preparation E472c, 0.5 g of amikacin powder is added as a surfactant. Then 5 ml of butyl chloride are added dropwise. The resulting suspension of nanocapsules is filtered and dried.

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

EXAMPLE 6. Obtaining nanocapsules of the sodium salt of benzylpenicillin, the ratio of core: shell 1: 3

0.5 g of benzylpenicillin sodium salt powder is added to a suspension of 1.5 g of gellan gum in hexane and 0.01 g of the preparation E472c as a surfactant. Then 5 ml of butyl chloride are added dropwise. The resulting suspension of nanocapsules is filtered and dried.

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

EXAMPLE 7. Obtaining nanocapsules of streptocide, the ratio of the core: shell 1: 3

To a suspension of 1.5 g of gellan gum in hexane and 0.01 g of the preparation E472c, 0.5 g of streptocide powder is added as a surfactant. Then 5 ml of butyl chloride are added dropwise. The resulting suspension of nanocapsules is filtered and dried.

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

EXAMPLE 8. Obtaining nanocapsules of ampicillin, the ratio of core: shell 1: 3 (see Fig. 2)

In a suspension of 1.5 g of gellan gum in hexane and 0.01 g of the preparation E472c, 0.5 g of ampicillin powder is added as a surfactant. Then 5 ml of butyl chloride are added dropwise. The resulting suspension of nanocapsules is filtered and dried.

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

EXAMPLE 9. Obtaining nanocapsules of kanamycin, the ratio of the core: shell 1: 3

0.5 g of kanamycin powder is added to a suspension of 1.5 g of gellan gum in hexane and 0.01 g of the preparation E472c as a surfactant. Then 5 ml of butyl chloride are added dropwise. The resulting suspension of nanocapsules is filtered and dried.

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

EXAMPLE 10. Obtaining nanocapsules of streptomycin, the ratio of the core: shell 1: 3

In a suspension of 1.5 g of gellan gum in hexane and 0.01 g of the preparation E472c, 0.5 g of streptomycin powder is added as a surfactant. Then 5 ml of butyl chloride are added dropwise. The resulting suspension of nanocapsules is filtered and dried.

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

EXAMPLE 11. Obtaining nanocapsules of bicillin-3, the ratio of the core: shell 1: 3

In a suspension of 1.5 g of gellan gum in hexane and 0.01 g of the preparation E472c, 0.5 g of bicillin-3 powder is added as a surfactant. Then 5 ml of butyl chloride are added dropwise. The resulting suspension of nanocapsules is filtered and dried.

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

EXAMPLE 12. 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 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 was 215 s, and the use of a syringe pump.

Nanocapsules of antibiotics in gellan gum were obtained by the physicochemical method of precipitation with a non-solvent using butyl chloride as non-solvents. The process is simple to execute and lasts for 15 minutes, does not require special equipment.

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

Claims (1)

A method of encapsulating a drug with a non-solvent precipitation method, characterized in that antibiotics are used as nanocapsule nuclei, gellan gum as a shell with a shell: core ratio of 3: 1, while Gellan gum in hexane in the presence of E472c as a surface-active substances add antibiotic powder, then butyl chloride is poured dropwise, the resulting suspension of nanocapsules is filtered off and dried.

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