EA035605B1 - Method of preparing a composition to produce capsules (embodiments) - Google Patents

Abstract

The invention relates to chemical and pharmaceutical industry and concerns creation of a new composition of agar and/or gelatin masses for the manufacture of capsules filled with oil-soluble substances on a hydrophobic base, dispersed oil emulsions, and biologically active biomass or drugs. The achieved result is an increase in quality of agar or gelatin capsules through improvement of antimicrobial protection and light protection of valuable bioorganic substances (capsule fillings). This result is achieved by provision of a method for preparing a composition to produce capsules, wherein, in the first embodiment, sodium humate is added in the form of a 0.5-5.0% solution, sodium humate solution and glycerin are introduced into the reactor, heated to 60-65°C and stirred, then agar-agar is added, stirred and heated to 90-95°C, the molten mass is deaerated, and then kept at the atmospheric pressure for 12 h at a temperature of 65-75°C, with the following ratio of components, wt.%: agar-agar - 5-8; glycerin - 8-13; sodium humate - 0.5-2.5; water - the balance. The second embodiment of the method is characterized by that sodium humate is added in the form of a 0.5-5.0% solution, and gelatin is used as a gel-forming agent, wherein sodium humate solution and glycerin are introduced into the reactor, heated to 60-75°C and stirred, then gelatin is added, stirred and heated to 75-80°C, the molten mass is deaerated, and then kept at the atmospheric pressure for 12 h at a temperature of 65-70°C, with the following ratio of components, wt.%: gelatin – 30-42; glycerin – 8-13; sodium humate - 0.5-2.5; water - the balance.

Description

The invention relates to the pharmaceutical industry and concerns the creation of a new composition of agar or gelatinous masses for the manufacture of capsules filled with oil-soluble substances on a hydrophobic basis, dispersed oil emulsions, as well as biologically active biomass or drugs.

Among the dosage forms, capsules are one of the most rapidly developing areas of pharmacy. Currently, preparations in the form of gelatin capsules occupy up to 20% of the nomenclature in countries with a developed pharmaceutical industry.

Conclusion of a solution or a homogeneous suspension of an active substance in capsules is especially valuable for the production of dosage forms containing a small amount (small dosage) of an active substance.

The high bioavailability of the active substance in the form of agar or gelatin capsules can become the basis for reducing the therapeutic dose, reducing and reducing possible side effects and, of course, financial costs.

Medicines that are sensitive to the effects of oxygen, in the case of using the technology for the production of agar or gelatin capsules, are protected from its effects, which allows to increase the shelf life of the drug - vitamins and plant products are an excellent example of this.

A known method of producing an enteric capsule with a shell made of agaragar and substances that improve the structural, mechanical and biopharmaceutical properties, namely sodium citrate, citric acid, glycerin and / or sorbitol. These capsules are filled with oil solutions of fat-soluble vitamins, and / or oil extracts from plant and / or animal raw materials, and / or fatty oils, and / or their mixtures (RF patent No. 2569742, class A61K 9/48, 2015).

The disadvantage of this composition is the presence of sorbitol for antimicrobial protection, as well as the lack of light-protective function, which does not prevent the destruction of the pharmaceutical agent placed in the capsule from the action of light.

A known method of obtaining a gelatinous mass, providing for mixing gelatin with auxiliary substances: preservatives, stabilizers, dyes, swelling of gelatin, melting, cooling the gelatinous mass, holding under vacuum and filtering the gelatinous mass. Used as a stabilizer and preservative, hydrogen peroxide is introduced into the gelatinous mass at all technological stages in an amount that provides the value of the redox potential of the mass of 0.30-0.40 V (RF patent No. 2095068, class A61K 35/32, 1997).

The main factors limiting the use of gelatin capsules are the susceptibility of gelatin to microbial contamination, destruction or change in shape under the influence of direct sunlight, at temperatures above 40 ° C or at humidity above 75%.

A known method of obtaining a composition for the manufacture of capsules, in which the plasticizer is added to water, stirred until dissolved, then agar-agar is added, left to swell at 15-40 ° C for 0.1-10 hours, preferably for 0.5-2 hours , after which the resulting mixture is stirred at a temperature of 70-99 ° C, preferably at a temperature of 80-98 ° C until the mixture becomes homogeneous and transparent. Dissolve zinc lactate or zinc sulfate in water before adding agar-agar. Glycerin is used as a plasticizer. The solution for encapsulation is fed to the encapsulation plant, where the capsules are extruded at a temperature of 77-99 ° C, preferably at 82-90 ° C, the encapsulation rate is 1-10 capsules / s, preferably 3-6 capsules / s, the temperature of the cooling liquid is 3 -15 ° C. The components are taken in the following ratio, wt%: agar-agar - 2-12; glycerin - 112; zinc lactate or zinc sulfate - 0.01-1.5; distilled water - the rest (RF patent No. 2405542, class A61K 9/48, 2010).

The disadvantage of this composition is the weak antimicrobial protection, as well as the lack of light-protecting function, which does not prevent the destruction of the pharmaceutical agent placed in the capsule from the action of light.

The objective of the invention is to create a new composition of agar or gelatinous masses for the manufacture of capsules filled with drugs, including oil-soluble substances on a hydrophobic basis, dispersed oil emulsions, as well as biologically active biomass.

The achieved result is an increase in the quality of agar or gelatin capsules by improving antimicrobial protection and light protection of valuable bioorganic substances (capsule fillings).

This result is achieved by the fact that in the first embodiment of the method for preparing a composition for the manufacture of capsules, including the introduction of agar-agar into a solution and glycerol and mixing the resulting mixture with heating, while the amount of agar-agar is 5.0-8.0 wt %, according to the invention, sodium humate is additionally introduced in the form of a 0.5-5.0% solution, while the sodium humate solution and glycerin are introduced into the reactor, heated to 60-65 ° C and stirred, then agar-agar is added, stirred and heated to 90-95 ° C, air is removed from the molten mass, and then kept at atmospheric pressure for up to 12 hours at a temperature of 65-75 ° C, with the following ratio of components, wt%: agar-agar - 5-8; glycerin - 8-13; sodium humate - 0.5-2.5; water is the rest.

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The second variant of the method for preparing a composition for the manufacture of capsules, including the introduction of a gelling agent into a glycerol solution and stirring the resulting mixture with heating, is characterized in that sodium humate is additionally introduced in the form of a 0.5-5.0% solution, and gelatin is used as a gelling agent , while a solution of sodium humate and glycerin are introduced into the reactor, heated to 60-75 ° C and stirred, then gelatin is added, stirred and heated to 7580 ° C, air is removed from the molten mass, and then kept at atmospheric pressure for up to 12 hours at temperature 65-70 ° C, with the following ratio of components, wt.%: gelatin - 30-42; glycerin - 8-13; sodium humate - 0.5-2.5; water is the rest.

In each of the method variants, when preparing a sodium humate solution, sterilization of water or a finished solution is carried out.

A distinctive feature of the proposed method of obtaining a composition for the manufacture of capsules is the introduction of water only in the form of a ready-made solution of sodium humate. Taking into account the fact that solutions based on humic acids are solutions of high molecular weight compounds, that is, polyampholytes, this makes the method very functional. That is, the demanded qualities of the capsules are achieved.

The inclusion in the composition of the sodium humate solution provides antimicrobial protection of the capsule and increases its light-protecting function.

It is sodium humate that serves as a preservative in the composition of agar or gelatinous masses instead of traditional potassium sorbate, nipagin, nipazole, sodium metabisulfite, salicylic acid.

At the same time, sodium humate is a light-protective dye, which is especially important for light-sensitive biologically active substances contained in the capsule, such as plant carotenoids (beta-carotene, phycocyanin, astaxanthin), vitamins. It is light protection that is an important tool in the preservation of vegetable oils, in particular olive oil, sunflower oil, sea buckthorn oil or rosehip oil.

A solution of sodium humate is an environmentally friendly product of natural origin and has high activity against a wide class of substances of organic and mineral nature, has a tonic effect, activates all types of metabolism, carbohydrate and protein metabolism, increases the utilization rate of nutrients in food, stimulates the vital activity of microflora intestines, accelerates the growth and development of the body of children and adolescents, increases the natural resistance of the body. Promotes a better synthesis reaction, normalizes the acid balance in the body. Sodium humate has pronounced antimicrobial, antifungal and antiviral properties, which makes it in demand in the production of agar or gelatin capsules.

Sodium humate solution is an organic aqueous composition of humic and fulvic acids. When hydrated, they can form quite stable colloidal systems. In an alkaline medium, ionization of the carboxyl group occurs, and in the region of high alkalinity and hydroxyl groups of phenolic fragments. The resulting system is usually called humate, and in a particular case, if an aqueous solution of sodium hydroxide acts as a solvent, sodium humate. Considering that solutions of humic acids are polyampholytes, it is possible to determine the isoelectric point of solutions, which is important for understanding many processes of their interaction with agar-agar or gelatin (Zhinzhilo V.A., Journal of Advances in Modern Natural Science, 2017, No. 9, p. 7- 12).

Sodium humate is a very effective protector against photodamage. The processes of detoxification of aqueous media in the presence of humic acids have been studied (Sokolova IV, Chaikovskaya ON Influence of humic acids on photoprocesses in aqueous media. Journal Vestnik Tomsk State Pedagogical University 2008, Issue 4 (78) pp. 42-46).

Oils suitable for use in this formulation, i.e. for placing inside humic agar or gelatin capsules, include, but are not limited to, olive oil, soybean oil, canola oil, sunflower oil, macadamia oil, peanut oil, grape seed oil. , pumpkin seed oil, linseed oil, corn oil, safflower oil, sesame oil, pine oil, conjugated linoleic acid, almond oil, peach oil, apricot oil, walnut oil, rapeseed oil, raspberry oil, blueberry oil, cranberry seed oil, oil from pomegranate seeds and oils from other fruit seeds, sea buckthorn oil, chia oil, perilla oil, diaglycerin (DAG) oil, oils derived from vegetables, omega 3 sources, fermented sources of eicosapentaenoic acid (EPA), fermented sources of docosahexaenoic acid (DHA) ), fermented sources of combinations of EPA, DHA and other omega 3s, including fish oil and krill oil, brine shrimp oil and pigments, sources gamma-linolenic acid (GLA) and / or stearidonic acid (SA), fractionated coconut oil, and combinations thereof. Sources of DHA, EPA and GLA from unicellular microalgae (chlorella, spirulina, hematococcus). Sources of probiotics to be placed in capsules.

Capsules from the proposed variants of the composition can be made by the rotary matrix method and have various shapes: round, oval, ovoid, cylindrical. At the same time, it is possible to manufacture a shell from two halves, both identical and different in color.

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The specified ratio of components is optimal. Deviation from the stated amounts of the components of the composition leads to the production of low-quality capsules, while such basic indicators as viscosity and moisture content change. The optimal content of gelatin and glycerin determines the elasticity of the film and the manufacturability of the final product. When the gelatin content is below 30%, the gelatinous mass is obtained with a viscosity below 45 s, which does not provide the possibility of producing high-quality capsules. An increase in the gelatin content above 42% leads to the production of a gelatinous mass with a viscosity of more than 2 minutes, which also does not provide the technological possibility of manufacturing capsules.

The content of glycerin in the composition of the gelatinous mass below 8% leads to the production of an inelastic film, which is unsuitable for the formation of the capsule shell. An increase in the glycerin content of more than 13% leads to a too soft shell, the capsules are easily deformed and do not keep their shape.

The content of agar-agar in an amount of 5-8% is also optimal for obtaining a high-quality composition.

It is also known that manufacturers are trying to reduce the preservative content, but this leads to a weak preservative effect, and an increase above 0.25 wt.% Causes irritation of the mucous membrane.

Sodium humate used as a preservative does not have such restrictions on the percentage in the composition. Sodium humate itself is known as a drug of pronounced pharmaceutical action: the active ingredients of sodium humate are humic and fulvic acids. Humic acid (HA) is a large, long chain of molecules. The complex of humic and fulvic acids is an extremely powerful combination for healing the body. This complex contains a full range of minerals, amino acids and trace elements, about 70 useful components in total. Such a rich polymorphic structure determines the variety of positive biological effects of humic acids. Due to carboxyl, carbonyl and aromatic fragments, humic acids enter into ionic, donor-acceptor and hydrophobic interactions, i.e. are able to bind various classes of ecotoxicants, forming complexes with metals and compounds with various classes of organic substances. They have catalytic activity, which is determined by the summation of enzymatic and non-enzymatic catalysis, which demonstrates their high biochemical potential. They have an anti-inflammatory effect - they regulate the number and ratio of T- and B-lymphocytes, activate the synthesis of interleukins IL-1, IL-2, induction of endogenous interferon, gamma globulins, which leads to activation of the suppressed functions of the immune system (low molecular weight acids inhibit protease activity).

The positive effect of humic acids on the human immune system has been shown. The use of derivatives of humic acids stimulates T-lymphocytes of both helper and suppressor subpopulations. The general regulatory mechanism of immune homeostasis is enhanced under the influence of neurohumoral-humoral rearrangements in the body, especially the systems of the hypothalamus - pituitary - adrenal cortex, adrenal cortex - thymus - spleen - lymph nodes, which is accompanied by the restoration of autoregulation of the immune response with a tendency to normalize disturbed lymphoid cells. The ability of humic acids to stimulate nonspecific resistance is associated with an increase in lysozyme, bactericidal, and neutrophilic activity of blood.

The antiviral activity of humic acids has been proven. The spectrum of viruses sensitive to humic acids includes numerous DNA and RNA viruses, herpes simplex viruses type 1 and 2 (HSV-1, HSV-2), cytomegalovirus, influenza virus types A and B, Coxsackie virus, human immunodeficiency virus, hemorrhagic fever virus, atypical pneumonia coronavirus.

As for the internal use of humic and fulvic acids, they can be useful in the prevention, treatment and elimination of the consequences of many gastric and intestinal diseases, such as hyperacidity, diarrhea, gastritis, dysentery, gastroenteritis and colitis. They can also act as detoxifiers and be used against microbial and viral infections. They have been found to be useful in the treatment of anemia, as an immune system stimulant and hepatoprotective agent. As a factor inhibiting the growth of some cancer cells, humic and fulvic acids have good prospects as anticancer agents.

Humic substances have a wide range of biological properties, which are already widely used and can be used in various fields of medicine. In particular, such drugs affect the nonspecific and specific resistance of the body, have antioxidant, anti-inflammatory, antiviral, antibacterial, antifungal, membranotropic, hepatoprotective properties, the ability to enhance the activity of metabolic processes in the body. Sodium humate contributes to the prevention of serotonin ulcers, increases the body's resistance to hypoxia. Humic substances are non-toxic, do not possess teratogenic, embryotoxic and carcinogenic properties.

The method is implemented as follows.

Example 1. Selected quantitative ratios of gelatin and glycerin in combination with 1%

- 3 035605 sodium humate solution make it possible to obtain soft gelatin capsules, in particular filled with dispersed olive oil and spirulina microalgae biomass by a rotational matrix method. A gelatinous mass based on these components is prepared as follows.

4 l of a 1% sodium humate solution and 2 kg of glycerin are fed into the reactor, the mixture is brought to 60-65 ° C and stirred. Then add 5 kg of gelatin grade P-11 of Halal standard and mix under vacuum at a residual pressure of 0.2-0.3 kgf / cm ² Then the mass is heated to 75-80 ° C and the gelatin is melted. The molten mass is evacuated to remove air at a residual pressure of 0.2-0.3 kg / cm ² and a temperature of 75-80 ° C for 1-2.5 hours. Then the mass is kept for 12 hours at 65-70 ° C without vacuum.

The finished gelatinous mass is sent to a thermostat, where the temperature is maintained at 55-65 ° C. The resulting mass has the following indicators: moisture content - 28-34%; relative viscosity - from 45 s to 2 min.

From the prepared mass, prototypes of high-quality soft gelatin capsules of black color were obtained by the rotational matrix method, containing as an active substance a dispersed emulsion of olive oil and living biomass of microalgae Spirulina. Thus, the use of sodium humate solution made it possible to obtain a new composition of gelatinous masses for the manufacture of capsules by the rotational matrix method.

Example 2. Prepared gelatin capsules on an automatic rotary matrix apparatus (Softgel encapsulator machine / DY-SG150). These machines can produce a very wide range of capsules in shape and size (Round # 3, Round # 5, Round # 7, Oval # 4, Oval # 6, Oval # 7.5, Oval # 10, Oblong # 5, Oblong # 11, Oblong # 16, Oblong # 20). The production of gelatin capsules itself is divided into stages / stages:

1) preparation of gelatinous mass;

2) production (molding) of gelatinous tapes (casings);

3) filling capsules;

4) their processing;

5) quality control / standardization.

In the production of gelatin capsules, the most important part (on which all the rest of the work depends) is to ensure the quality and technology of preparing the gelatin mass, the basis for obtaining capsules. The gelatinous mass must have certain physicochemical properties, which depend on the quality of the gelatin and the ingredients (plasticizers, glycerin, antimicrobial drugs, preservatives and water).

According to one of the processes for preparing the composition, a sterile cold 2% sodium humate solution with a temperature of 15-18 ° C is poured into a gelatinous thermostatted reactor, food glycerin of plant origin is added (a by-product in the production of biodiesel in Germany) and the temperature is brought to 75 ° C, after which gelatin (brand K-13 of the Halal standard) is added to the reactor with the stirrer running and the stirring process is left in the operating mode for 1 or 2 hours. The reactor must be equipped with a water jacket with auto-thermostatic control (temperature indication on a digital display).

After turning off the stirrer, the heating is reduced from a temperature of 75-80 ° C to 60 ° C and left for 10-12 hours to remove air bubbles from the mass. In the presence of a vacuum device (due to the pump), the same process (removal of air bubbles from the mass) can be carried out over a period of 2-4 hours. Before the start of encapsulation, the viscosity of the gelatinous mass is controlled. This technology is associated with a high concentration of gelatin and is usually used to obtain capsules by pressing.

Example 3. To prepare a gelatinous mass without swelling, a calculated volume of purified water is introduced into a closed reactor equipped with a water jacket, an automatic temperature controller and a paddle stirrer and heated to 70-75 ° C. In a heated 2% sodium humate solution, glycerin is sequentially dissolved, after which gelatin of the K13 brand is loaded with the mixer turned on. Stir until it is completely dissolved. Then they proceed in the same way as when receiving a mass with the process of swelling of gelatin, control the time parameters of the dissolution of gelatin, the operation of the mixer and stabilization of the gelatin mass.

The encapsulation process takes place under the conditions of thermostating the gelatinous mass at a temperature of at least 40-45 ° C.

The selected quantitative ratios of gelatin and glycerin in combination with a 2% sodium humate solution make it possible to obtain black soft gelatin capsules, in particular, filled with dispersed olive oil and chlorella microalga biomass by a rotational matrix method. A gelatinous mass based on these components is prepared as follows.

8 L of a 2% sodium humate solution and 4 kg of glycerin are fed into the reactor, the mixture is brought to 60-65 ° C and stirred. Then add 10 kg of gelatin grade K-13 and mix under vacuum at a residual pressure of 0.2-0.3 kgf / cm ² . Then the mass is heated to 75-80 ° C and the gelatin is melted. The molten mass is evacuated to remove air at a residual pressure of 0.2-0.3 kg / cm ² and a temperature of 7580 ° C for 1-2.5 hours. Then the mass is kept for 12 hours at 65-70 ° C without vacuum.

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The finished gelatinous mass is sent to a thermostat, where the temperature is maintained at 55-65 ° C. The resulting mass has the following indicators: moisture content - 28-34%; relative viscosity - from 45 s to min.

From the prepared mass, experimental samples of black soft gelatin capsules were obtained by the rotational matrix method, containing dispersed olive oil and chlorella microalgae biomass as an active substance. Thus, the use of sodium humate solution made it possible to obtain a new composition of gelatinous masses for the manufacture of capsules by the rotational matrix method, containing dispersed olive oil and the biomass of the microalgae chlorella as an active substance.

Example 4. The gelatinous mass is prepared as follows.

A 3% sodium humate solution and glycerin are fed into the reactor, the mixture is brought to 60-65 ° C and stirred. Then add gelatin grade P-11 Halal standard and mix under vacuum at a residual pressure of 0.2-0.3 kgf / cm ² . Then the mass is heated to 75-80 ° C and the gelatin is melted. The molten mass is evacuated to remove air at a residual pressure of 0.2-0.3 kg / cm ² and a temperature of 75-80 ° C for 1-2.5 hours. Then the mass is kept for 12 hours at 65-70 ° C without vacuum.

The finished gelatinous mass is sent to a thermostat, where the temperature is maintained at 55-65 ° C. The resulting mass has the following indicators: moisture content - 28-34%; relative viscosity - from 45 s to 2 min.

From the prepared mass, prototypes of black soft gelatin capsules were obtained by the rotary matrix method, containing dispersed olive oil and sodium humate as an active substance.

Example 5. Into the reactor 4 l of 1% sodium humate solution and 2 kg of glycerin are fed, the mixture is brought to 60-65 ° C and stirred. Then add 5 kg of gelatin grade K13 Halal standard and mix under vacuum at a residual pressure of 0.2-0.3 kgf / cm ² . Then the mass is heated to 75-80 ° C and the gelatin is melted. The molten mass is evacuated to remove air at a residual pressure of 0.2-0.3 kg / cm ² and a temperature of 75-80 ° C for 1-2.5 hours. Then the mass is kept for 12 hours at 65-70 ° C without vacuum.

The finished gelatinous mass is sent to a thermostat, where the temperature is maintained at 55-65 ° C. The resulting mass has the following indicators: moisture content - 28-34%; relative viscosity - from 45 s to 2 min. The molten gelatinous mass enters through a heated pipeline into the orifice assembly, which is a conical tubular nozzle, from where it is pushed out simultaneously with the supply of the drug (dispersed Artemia biomass in olive oil) through the dosing device, which fills the capsule as a result of a two-phase concentric flow. With the help of a pulsator, the droplets are torn off and fed to a cooler, which is a circulation system for forming, cooling and mixing capsules.

The formed capsules fall into chilled vaseline oil (14 ° C), undergoing a circular pulsation, acquire a strictly spherical shape. The capsules are separated from the oil, washed in 96% ethanol and dried in special chambers (air flow rate 3 m / s), which allows you to quickly remove moisture from the capsule shell. The method is characterized by full automation, high productivity (28-100 thousand capsules / h), dosage accuracy of the drug (± 3%), hygiene and economy of gelatin consumption. This drip method is very convenient for encapsulating fat-soluble vitamin complexes. Drip capsules are easily recognizable by the absence of a seam on them. From the prepared mass, prototypes of soft, seamless gelatin capsules of black color with a spherical shape were obtained, containing dispersed olive oil and Artemia biomass as an active substance.

Example 6. Into the reactor 4 l of 1% sodium humate solution and 2 kg of glycerin are fed, the mixture is brought to 60-65 ° C and stirred. Then add 5 kg of gelatin grade K13 Halal standard and mix under vacuum at a residual pressure of 0.2-0.3 kgf / cm ² . Then the mass is heated to 75-80 ° C and the gelatin is melted. The molten mass is evacuated to remove air at a residual pressure of 0.2-0.3 kg / cm ² and a temperature of 75-80 ° C for 1-2.5 hours. Then the mass is kept for 12 hours at 65-70 ° C without vacuum.

The finished gelatinous mass is sent to a thermostat, where the temperature is maintained at 55-65 ° C.

A gelatinous mass heated to a temperature of 40-70 ° C (with an external stream) and a filler (with an internal stream) are supplied to the nozzle assembly of the capsulator under air pressure. The formation of capsules occurs directly at the outlet of the orifice assembly: the jet is separated under the influence of pulsating oil, and the separated part, due to the force of the surface tension of the gelatinous mass, smoothly takes on a spherical shape. In a weak flow of vegetable oil cooled to a temperature of 5-12 ° C, the shells of the formed capsules gradually solidify. The flow rate of the gelatinous mass and filler is regulated by changing the air (or nitrogen) pressure. The result of this process is ready-made gelatin capsules with a filler weight of 0.03-0.8 g, and a diameter ranging from 4 to 13 mm. The air in the encapsulation area should have a temperature of 20-21 ° C and a relative humidity of 50-75%. 20-30 minutes after switching on, the transport oil in the capsule system is cooled to 5-10 ° C. To prevent contact of capsules with air, about 2-2.5 liters of vegetable oil are poured into the container. Upon completion of the encapsulation, containers with capsules are moved to

- 5 035605 refrigerating chamber (humidity 55-65% and air temperature 10-12 ° C). The capsules are kept in the refrigerating chamber from 12 to 24 hours. The next stage is to squeeze out the remaining vegetable oil (in a centrifuge). The centrifuge can be loaded for squeezing 3-5 kg of soft gelatin capsules. For the capsule drying process, it is necessary to maintain the air temperature in the room within 18-20 ° C, the relative humidity can vary within 40-55%. From the prepared mass, prototypes of soft, seamless gelatin capsules of black color with a spherical shape were obtained, containing dispersed olive oil and Artemia biomass as an active substance.

Example 7. In the reactor served 9 l of a 1% solution of sodium humate and 0.5 kg of glycerin, bring the mixture to 60-65 ° C and stirred. Then add 0.5 kg of agar-agar (E-406) and mix under vacuum at a residual pressure of 0.2-0.3 kgf / cm ² . Then the mass is heated to 95 ° C and the agar-agar is melted. The molten mass is evacuated to remove air at a residual pressure of 0.2-0.3 kg / cm ² and a temperature of 75-80 ° C for 2.5 hours. Then the mass is kept for 12 hours at 70-75 ° C without vacuum. The finished agar mass is sent to a thermostat, where the temperature is maintained at 70-75 ° C.

Agar mass heated to a temperature of 80 ° C (external jet) and filler (internal jet) are supplied to the nozzle assembly of the capsulator under air pressure. The formation of capsules occurs directly at the outlet of the orifice unit: the jet is separated under the influence of pulsating oil, and the separated part smoothly takes on a spherical shape due to the force of the surface tension of the agar mass. In a weak flow of vegetable oil cooled to a temperature of 20-25 ° C, the shells of the formed capsules gradually solidify. The consumption of agar mass and filler is regulated by changing the air (or nitrogen) pressure. The result of this process is ready-made agar capsules with a filler weight of 0.03-0.8 g, and the diameter varies from 4 to 13 mm. The air in the encapsulation area should have a temperature of 20-25 ° C and a relative humidity of 5075%. 20-30 minutes after switching on, the transport oil in the capsule system is cooled to 20 ° C. To prevent contact of capsules with air, about 2-2.5 liters of vegetable oil are poured into the container. Upon completion of the encapsulation, the containers with the capsules are moved to the refrigerating chamber (humidity 55-65% and air temperature 20-21 ° C). The capsules are kept in the refrigerating chamber from 12 to 24 hours. The next stage is to squeeze out the remaining vegetable oil (in a centrifuge).

The centrifuge can be loaded for squeezing 3-5 kg of soft agar capsules. For the capsule drying process, it is necessary to maintain the air temperature in the room within 18-20 ° C, the relative humidity can vary within 40-55%. From the prepared mass, test samples of soft seamless agar capsules of black color, spherical, were obtained, containing dispersed olive oil and spirulina biomass as an active substance.

Capsules with a bioactive organic filling can also be made from a dispersed emulsion of olive oil and chlorella biomass, or from a dispersed emulsion of olive oil and artemia biomass, or from a dispersed emulsion of olive oil and astaxanthin (hematococcus biomass).

Example 8. In a gel reactor (volume 20 l) 1 kg of agar-agar (E-406) is fed, poured with 2% sodium humate solution (18 l) and left for 30 minutes. Then the mixture is brought to 95 ° C, stirred until the agar is completely melted. Glycerin 1800 g, sodium citrate - 340 g, table (sea salt) - 60 g, citric acid - 40 g are added to the hot agar / gel mixture.

The molten mass is evacuated to remove air at a residual pressure of 0.2-0.3 kg / cm ² and a temperature of 75-80 ° C for 2.5 hours. Then the mass is kept for 12 hours at 90 ° C without vacuum. The finished agar mass is sent to a thermostat, where the temperature is maintained at 90 ° C.

Agar gel for the manufacture of capsules consists (in wt.%): Agar-agar - 5; glycerin - 9.0; sodium humate - 1.8; sodium citrate - 1.7; sodium chloride (food salt / sea salt not iodized) - 0.2; citric acid - 0.25; water - the rest (up to 100%).

Agar mass heated to a temperature of 90 ° C (with an external stream) and a filler (with an internal stream) are supplied to the nozzle assembly of the capsulator under air pressure. The formation of spherical seamless capsules occurs directly at the outlet of the orifice unit: the jet is separated under the influence of pulsating oil, and the separated part smoothly acquires a spherical shape due to the force of surface tension of the agar mass. In a weak flow of vegetable oil cooled to a temperature of 20-25 ° C, the shells of the formed capsules gradually solidify. The consumption of agar mass and filler (dispersed olive oil with spirulina biomass) is regulated by changing the air (or nitrogen) pressure. The result of this process is ready-made agar capsules with a filler weight of 0.03-0.8 g, and the diameter varies from 4 to 13 mm. The air in the encapsulation area should have a temperature of 20-25 ° C and a relative humidity of 50-75%. In 20-30 minutes after turning on the capsulator, the transport oil in its system is cooled to 20 ° C. To prevent contact of capsules with air, about 2-2.5 liters of vegetable oil are poured into the container. Upon completion of the encapsulation, the containers with the capsules are moved to the refrigerating chamber (humidity 5565% and air temperature 20-21 ° C). The capsules are kept in the refrigerating chamber from 12 to 24 hours. The next stage is to squeeze out the remaining vegetable oil in a centrifuge.

The centrifuge can be loaded for squeezing 3-5 kg of soft agar capsules. For the drying process

- 6 035605 capsules, it is necessary to maintain the air temperature in the room within the range of 18-20 ° C, the relative humidity can vary within the range of 40-55%. Then the capsules are ground. The agar capsule grinding process is necessary to remove oils and other contaminants from the capsule surface. For this, agar capsules are placed in a container, filled with isopropyl or ethyl alcohol, keeping with constant stirring for 10-15 minutes. Then the capsules are unloaded into a grid, the liquid is allowed to drain, poured onto a grid lined with parchment, and dried in a cabinet. An additional second drying is carried out to remove the solvent for 3 hours with air at 22-25 ° C. After that, the capsules are again filled with ethyl or isopropyl alcohol and stirred for 5 minutes. Then the capsules are poured onto trays (lattices) lined with clean parchment and dried at 20-22 ° C with air for 2 hours to bring the moisture content of the shells to 8-10%. Then the dried agar capsules are packed into jars.

To regenerate the rejected capsules, they are cut and the shells are separated from the drug solution using a centrifuge. The casings are regenerated and put into capsule production separately.

From the prepared agar mass, experimental samples of soft seamless agar capsules of black color with a spherical shape were obtained, containing dispersed olive oil and spirulina biomass as an active substance.

Example 9. In a gel reactor (volume 20 l) 1 kg of agar (E-406) is fed, poured with 1.5% sodium humate solution (18 l) and left for 30 minutes. Then the mixture is brought to 95 ° C, stirred until the agar is completely melted. Glycerin 1500 g, sodium citrate - 500 g, table or sea salt - 120 g, citric acid - 80 g are successively added to the hot agar gel mixture. The molten mass is evacuated to remove air at a residual pressure of 0.2-0.3 kg / cm ² and a temperature of 75-80 ° C for 2.5 hours. Then the mass is kept for 12 hours at 90 ° C without vacuum. The finished agar mass is sent to a thermostat, where the temperature is maintained at 90 ° C. Agar gel for the manufacture of capsules consists (wt.%): Agar-agar (E-406) - 5; glycerin - 8.0; sodium humate - 1.35; sodium citrate - 2.5; sodium chloride - 0.4; citric acid - 0.5; water is the rest.

Agar mass heated to a temperature of 90 ° C (with an external stream) and a filler (with an internal stream) are supplied to the nozzle assembly of the capsulator under air pressure. The formation of spherical seamless capsules occurs directly at the outlet of the orifice unit: the jet is separated under the influence of pulsating oil, and the separated part smoothly acquires a spherical shape due to the force of surface tension of the agar mass. In a weak flow of vegetable oil cooled to a temperature of 20-25 ° C, the shells of the formed capsules gradually solidify. The consumption of agar mass and filler (dispersed olive oil with artemia biomass) is regulated by changing the air (or nitrogen) pressure. The result of this process is ready-made agar capsules with a filler weight of 0.03-0.8 g, and the diameter varies from 4 to 13 mm. The air in the encapsulation area should have a temperature of 20-25 ° C and a relative humidity of 50-75%. To prevent contact of capsules with air, about 2-2.5 liters of vegetable oil are poured into the container. Upon completion of the encapsulation, the containers with the capsules are moved to the refrigerating chamber (humidity 5565% and air temperature 20-21 ° C). The capsules are kept in the refrigerating chamber from 12 to 24 hours. After the remaining vegetable oil is squeezed out in a centrifuge, the capsules are ground and further dried, the finished capsules are packed into jars.

Example 10. In a gel reactor with a volume of 20 liters, 1 kg of agar-agar is fed, poured with 1.5% sodium humate solution (18 liters) and left for 30 minutes. Then the mixture is brought to 95 ° C, stirred until the agar-agar is completely melted. Glycerin 2000 g, sodium citrate - 500 g, table or sea salt - 120 g, citric acid - 80 g are added successively to the hot agar gel mixture. The molten mass is evacuated to remove air at a residual pressure of 0.2-0.3 kg / cm ² and a temperature of 75-80 ° C for 2.5 hours. Then the mass is incubated for 12 hours at 90 ° C without vacuum. The finished agar mass is sent to a thermostat, where the temperature is maintained at 90 ° C.

Agar gel for the manufacture of capsules consists (wt.%): Agar-agar (E-406) - 5; glycerin - 10.0; sodium humate - 1.35; sodium citrate - 2.5; sodium chloride - 0.4; citric acid - 0.5; water is the rest.

Agar mass heated to a temperature of 90 ° C (with an external stream) and a filler (with an internal stream) are supplied to the nozzle assembly of the capsulator under air pressure. The formation of spherical seamless capsules occurs directly at the outlet of the orifice unit: the jet is separated under the influence of pulsating oil, and the separated part smoothly acquires a spherical shape due to the force of surface tension of the agar mass. In a weak flow of vegetable oil cooled to a temperature of 20-25 ° C, the shells of the formed capsules gradually solidify. The consumption of agar mass and filler (dispersed olive oil with sodium humate and B. subtilus probiotic, this probiotic withstands heating and does not lose its activity at high temperatures and in gastric juice) is regulated by changing the air pressure (or nitrogen). The result of this process is ready-made agar capsules with a filler weight of 0.03-0.8 g, and the diameter varies from 4 to 13 mm. Further processing of capsules is carried out according to examples 8, 9.

From the prepared agar mass, experimental samples of soft seamless agar capsules of black spherical shape were obtained, containing dispersed olive oil, sodium humate and probiotic B. subtilis as an active substance.

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The B. subtilis bacterium is one of the most promising probiotics studied in recent decades. The mechanisms of its probiotic action are associated with the synthesis of antimicrobial substances, enhancement of nonspecific and specific immunity, stimulation of the growth of normal intestinal microflora and the release of digestive enzymes. The listed mechanisms of action make the use of B. subtilis as part of complex therapy to fight intestinal infections justified; prevention of respiratory infections during the cold season; prevention of antibiotic-associated diarrhea; for the correction of digestive disorders and the promotion of food of various origins (errors in the diet, changes in the diet, diseases of the gastrointestinal tract, disorders of the autonomic nervous system) B. subtilis usually does not cause side effects. This probiotic is characterized by a high ratio of effectiveness and safety.

Claims (4)

CLAIM 1. A method of obtaining a composition for the manufacture of capsules, comprising introducing agar-agar into a glycerol solution and stirring the resulting mixture with heating, the amount of agar-agar being 5.0-8.0 wt%, characterized in that sodium humate is additionally introduced in the form of a 0.5-5.0% solution, while a solution of sodium humate and glycerin is introduced into the reactor., heated to 60-65 ° C and stirred, then agar-agar is added, mixed and heated to 90-95 ° C, air is removed from the molten mass, and then kept at atmospheric pressure for up to 12 hours at a temperature of 65-75 ° C, with the following ratio of components, wt%: agar-agar - 5-8; glycerin - 8-13; sodium humate - 0.5-2.5; water is the rest. 2. The method according to claim 1, characterized in that during the preparation of the sodium humate solution, water or the finished solution is sterilized. 3. A method of obtaining a composition for the manufacture of capsules, comprising introducing a gelling agent into a solution of glycerin and stirring the resulting mixture with heating, characterized in that sodium humate is additionally introduced in the form of a 0.5-5.0% solution, and gelatin is used as a gelling agent , while a solution of sodium humate and glycerin are introduced into the reactor, heated to 60-75 ° C and stirred, then gelatin is added, stirred and heated to 75-80 ° C, air is removed from the molten mass, and then kept at atmospheric pressure up to 12 h at a temperature of 6570 ° C, with the following ratio of components, wt%: gelatin - 30-42; glycerin - 8-13; sodium humate - 0.5-2.5; water is the rest. 4. The method according to claim 3, characterized in that when preparing a sodium humate solution, sterilization of water or a finished solution is carried out.