RU2569742C1 - Enteric-coated soft capsule and method for producing it - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: capsules are filled with oily solutions of fat-soluble vitamins, and/or oil extracts from herbal and/or animal raw material, and/or fatty oils, and/or mixes thereof. The group of inventions also concerns a method for producing a solution used to prepare a coating of the above capsule, a method for producing the above capsule and a method for hardening the capsule coating.

EFFECT: enteric capsules with a swelling agar coating having the rheological and structural-mechanical properties as good as those of a gelatine coating, more resistant to humidity variations, making it possible to add water-soluble biologically active substances and produce agar capsules with the use of encapsulation equipment for soft gelatine capsules.

17 cl, 27 ex, 2 dwg

Description

The invention relates to the pharmaceutical industry, in particular to the creation of an enteric-coated capsule made from agar-agar with or without water-soluble biologically active substances and filled with oil solutions of fat-soluble vitamins and / or oil extracts from plant materials and / or fatty oils, and / or oil extracts from animal raw materials, and / or hydrophobic substances, and / or mixtures thereof. The composition of the capsule shell includes auxiliary water-soluble components to provide the required structural-mechanical and biopharmaceutical properties of the capsule shell — viscosity, fluidity, strength, stability under differences in moisture, and disintegration in the intestine.

Soft capsules remain the only dosage form capable of preserving and delivering lipophilic or hydrophobic biologically active substances in an easily accessible form for the body - a solution (2, 3).

The main factors limiting the use of gelatin capsules are: the gelatin's susceptibility to microbial contamination, capsules can break down or change their shape under direct sunlight, at a temperature of more than 40 ° C or at a humidity of more than 75% (4, 5), as well as restrictions on gelatin use due to the incidence of bovine spongiform encephalopathy and restrictions on the use by vegetarians and people who use halal and kosher food (6, 7).

In addition, gelatin capsules without additional processing are not suitable for substances that are destroyed in the stomach by acid (8). The disadvantage of gelatin-based soft capsules is that they are not suitable for encapsulating hygroscopic substances due to the high moisture content in the capsule shell (5).

In recent decades, scientists have attracted great interest in the development of soft gelatin capsules to improve the properties of capsules.

Known technologies for creating soft capsules based on non-gelatinous polymers such as starch, cellulose, dextrin, pullulan, gellan, mannan, polyvinyl alcohol and their derivatives, further comprising a gelling hydrocolloid, for example, carrageenan, alginate or guar gum (9-26).

When creating capsules by these methods, additional costs are required for the second gelling agent, selection of the optimal ratios of the two polymers, selection of a complexing agent to impart gelling properties (Ca ²⁺ , Na ⁺ , K ⁺ cations), which leads to a higher cost of technology and an increase in the cost of the final product. In addition, these technologies do not allow the preparation of enteric capsules, which is not suitable for encapsulating biologically active substances that are destroyed by the acidic environment of the stomach or lipophilic substances, the main absorption of which occurs in the small intestine.

In order to give the capsule the properties of solubility in the intestine, methods such as:

- applying film coatings to the finished capsule, as well as imparting enteric properties to the filler itself - enteric film coatings are applied directly to granules, pellets or microcapsules, which are coated in hard gelatin capsules after coating (27-33);

- obtaining a shell for enteric capsules based on cellulose derivatives, for example, hydroxypropyl methylcellulose (34-38).

The application of enteric coatings on capsules greatly complicates the technology, since it requires a separate production site for coating, as well as the encapsulation section, which is not economically viable. In addition, this technology is not suitable for lipophilic substances. The disadvantage of the technology of hydroxypropylmethyl cellulose capsules is that it consists in obtaining hard capsules and is not suitable for incorporating fat-soluble active substances without special additional expensive equipment.

There is a method for producing a shell for enteric capsules based on alginate (39-42). The disadvantage of these capsules is that, due to the specificity of the polysaccharide polymer, they have an unstable soft shell and are easily destroyed by mechanical stress. The creation of such a shell does not allow the production of drugs according to the technology for soft gelatin capsules, which leads to the creation of a new production line and economic losses.

The most suitable thickener and gelling agent, which forms elastic reversible gels and has the most suitable properties for encapsulation, is a polysaccharide - agar-agar.

In physical and chemical properties, it is similar to a polymer of protein origin - gelatin and therefore can be used as an alternative material for creating a capsule shell.

An invention is known for creating soft capsules having a shell based on hydrophilic polymers, including agar (43-45).

The disadvantage of these capsules is that their shell, without increasing its density, is easily destroyed by mechanical stresses and, therefore, difficulties arise in the production of capsules, since the washing process from the process oil is difficult and is accompanied by large losses, which is not economically feasible. Difficulties also arise in their packaging, transportation and storage. The shell of the obtained capsules based on agar-agar-containing material is poorly soluble in water even at high temperatures, so it is recommended to take the capsules sublingually. In addition, the parameters of the technological process for producing soft capsules based on agar are not indicated in the aforementioned method, and therefore it is impossible to evaluate the advantages of the technology of agar capsules.

Closest to the proposed invention is a soft agar capsule, in which water-soluble biologically active substances are included in the shell material, and fat-soluble substances are included in the core with the formation of a homogeneous phase in each of the structural elements of the capsule, and the combination of fat-soluble and water-soluble biologically active substances, in particular vitamins, provides a synergistic effect the drug as a whole. Disintegration time of capsules according to the requirements of the Pharmacopoeia of the USSR XI ed. in water is no more than 20 min (46).

The disadvantage is that the capsule shell is made of a polymeric substance agar-agar and a plasticizer, without the inclusion of additional excipients, allowing to bring the technological and biopharmaceutical properties of agar capsules to the properties of soft gelatin capsules and to ensure their solubility in the intestine.

In the production of these capsules, the structural-mechanical and technological parameters characteristic of gelatin capsules are not provided. This leads to the fact that it is necessary to change the technological process in production, which is not economically viable. In addition, the production of capsules based on agar-agar is accompanied by losses exceeding the losses of soft gelatin capsules.

The present invention is the creation of soft capsules having a swelling agar shell, so that structural and mechanical parameters it is not inferior to the gelatin shell, had a minimum amount of excipients and allowed dissolution in the intestine.

The problem is solved in that the known soft capsule consists of a shell of agar and a plasticizer containing at least one biologically active substance, and a solution of at least one biologically active substance in oil (46), according to the invention, for enteric coating excipients are pre-mixed with water, water-soluble biologically active substances and 1-10% thickener are added if necessary; capsules are prepared on a capsule intended for soft gelatin capsules, while filling them with oil solutions of biologically active substances, and / or solutions of fat-soluble vitamins, and / or oil extracts from vegetable and / or animal raw materials, and / or vegetable, fish oil oils, and / or mixtures thereof at a temperature of 70-99 ° C, the encapsulation rate of 1-20 capsules per second, the temperature of the coolant 3-15 ° C, incubated in a solution of monohydric alcohol for 0.1-10 minutes and dried.

We have experimentally established that it is preferable to use agar-agar polysaccharide in the amount of 1-10% as a polymer, and the capsule shell contains 0.1-5 masses as auxiliary substances providing optimal structural-mechanical and biopharmaceutical properties. % sodium citrate and 0.01-2 wt. % citric acid, as well as 1-10 mass. % glycerol and / or 0.1-1 mass. % sorbitol.

In addition, to increase strength, the mixture may contain sodium chloride salt, preferably in a concentration of 1-3%.

The mixture is left to swell at 15-40 ° C for 0.1-10 hours, preferably 0.5-2 hours, more preferably about 1 hour, after which the resulting mixture is dissolved at a temperature of 80-99 ° C, preferably at a temperature 90-98 ° C, until the mixture becomes homogeneous and transparent.

To give pharmacological properties, it is possible to add water-soluble biologically active substances to the shell composition. To do this, during the preparation of the solution for encapsulation, before adding the agar-agar, microelements, water-soluble plant extracts in an amount of 0.01-1.5% are dissolved in water, preferably at a temperature of 40-60 ° C. Dissolution is carried out until the mixture becomes homogeneous.

As a fat-soluble BAS, the core of the capsule may contain oily solutions of fat-soluble vitamins, such as vitamins A 0.01 to 20 wt. %, and / or vitamin E 0.1-50 wt. %, and / or vitamin D 0.01-20 wt. %, and / or vitamin K1 0.01-0.1 wt. %, and / or vitamin F (polyunsaturated fatty acids omega-3 and omega-6) 0.1-100 wt. %, and / or carotenoids (provitamin A or lycopene or astaxanthin or lutein or zeaxanthin or a mixture thereof) 0.01-20 wt. %, and / or coenzyme Q10 0.5-20 wt. %, and / or fish oil 0.1-100 wt. %, and / or selenoxanthene (selexen) 0.01-0.08 wt. %, and / or non-steroidal anti-inflammatory drugs (ibuprofen or ketoprofen or others) 5-70 wt. %, and / or a mixture of poly (dimethylsiloxane) and silicon dioxide 4-70 wt. %, and / or fatty oils of 0.1-100 wt. %, and / or lipid extracts from plant and / or animal raw materials 0.1-99.9 wt. %, and / or mixtures thereof, etc.

Experimental studies conducted by the authors revealed that it is rational to obtain capsules on a capsulator installation by extrusion or stamping, where they are molded and filled at a temperature of 70-99 ° C, preferably at 80-90 ° C, most preferably at 85 ° C. The encapsulation rate is 1-20 capsules per second, preferably 3-6 capsules per second. Coolant temperature 3-15 ° C.

In the production of capsules, we found that the encapsulation solution and the shell based on the agar-agar polymer with modifying additives do not differ in rheological and structural-mechanical properties from the shell of soft gelatin capsules. This allows you to produce agar capsules on capsule equipment without changing the process.

In addition, it was found that to increase the strength of the capsule shell and reduce losses at the stage, it is sufficient to maintain the capsules in a solution of monohydric alcohol, preferably in 95% ethanol, for 0.1-10 minutes. This technological method allowed to increase the strength of the shell, without using preliminary exposure to an aqueous solution of polyhydric alcohol.

Spherical or oblong capsules were obtained, having a smooth surface, without damage and visible air and mechanical inclusions, filled with an oily liquid. The disintegration time of the capsules met the requirements of GF XI, issue 2, p. 144 and EP 7.0, p. 708 for enteric capsules and in phosphate buffer solution was not more than 5 min at 37 ° C.

Compared with the technology of soft agar capsules (RU 2405542), the proposed method for producing agar capsules allows you to: reduce exposure in a solution of polyhydric alcohol, improve the structural and mechanical properties of capsules, reduce technological losses.

The obtained results make it possible to recommend soft capsules based on agar-agar for encapsulating lipophilic substances, protecting substances from the acidic environment of the stomach, and ensuring the release of active substances in the intestine, which is most preferred for lipophilic substances.

It was experimentally found that the shell of soft agar capsules is 3-4 times thinner than the shell of soft gelatin capsules.

To improve appearance, taste and stability, the capsule may additionally contain antioxidants, preservatives, flavorings, sweeteners, and colorants in the outer shell and / or core.

In addition, in this invention, the parameters of the technological process for producing soft enteric capsules based on agar-agar are indicated, and in this regard, the advantages of this technology can be evaluated.

Examples of capsule shells:

Example 1

For the manufacture of the shell used a pre-prepared solution containing, by weight. %:

Agar agar four Glycerol 2 Sodium citrate 0.8 Lemon acid 0.01 Distilled water Up to 100

Example 2

For the manufacture of the shell used a pre-prepared solution containing, by weight. %:

Agar agar four Glycerol 2 Sorbitol 0.5 Sodium citrate 2.0 Sodium chloride 1.7 Lemon acid 0.01 Distilled water Up to 100

Example 3

For the manufacture of the shell used a pre-prepared solution containing, by weight. %:

Agar agar four Glycerol 5 Sorbitol 0.5 Sodium citrate 2.0 Sodium chloride 0.6 Lemon acid 0.7 Distilled water Up to 100

Example 4

For the manufacture of the shell used a pre-prepared solution containing, by weight. %:

Agar agar four Glycerol 5 Sodium citrate 2.0 Lemon acid 0.7 Distilled water Up to 100

Example 5

For the manufacture of the shell used a pre-prepared solution containing, by weight. %:

Agar agar four Glycerol 3,5 Sorbitol 0.2 Sodium citrate 1,0 Lemon acid 0.5 Distilled water Up to 100

Example 6

For the manufacture of the shell used a pre-prepared solution containing, by weight. %:

Agar agar four Glycerol 3,5 Sorbitol 0.2 Sodium citrate 1,0 Sodium chloride 0.6 Lemon acid 0.5 Distilled water Up to 100

Example 7

For the manufacture of the shell used a pre-prepared solution containing, by weight. %:

Agar agar four Glycerol 3,5 Sorbitol 0.2 Sodium citrate 1,0 Sodium chloride 1.7 Lemon acid 0.5 Distilled water Up to 100

Example 8

For the manufacture of the shell used a pre-prepared solution containing, by weight. %:

Agar agar 5 Glycerol 2 Sodium citrate 0.8 Lemon acid 0.01 Distilled water Up to 100

Example 9

For the manufacture of the shell used a pre-prepared solution containing, by weight. %:

Agar agar 5 Glycerol 2 Sorbitol 0.5 Sodium citrate 2.0 Sodium chloride 1.7 Lemon acid 0.01 Distilled water Up to 100

Example 10

For the manufacture of the shell used a pre-prepared solution containing, by weight. %:

Agar agar 5 Glycerol 5 Sorbitol 0.5 Sodium citrate 2.0 Sodium chloride 0.6 Lemon acid 0.7 Distilled water Up to 100

Example 11

For the manufacture of the shell used a pre-prepared solution containing, by weight. %:

Agar agar 5 Glycerol 5 Sodium citrate 2.0 Lemon acid 0.7 Distilled water Up to 100

Example 12

For the manufacture of the shell used a pre-prepared solution containing, by weight. %:

Agar agar 5 Glycerol 3,5 Sorbitol 0.2 Sodium citrate 1,0 Lemon acid 0.5 Distilled water Up to 100

Example 13

For the manufacture of the shell used a pre-prepared solution containing, by weight. %:

Agar agar 5 Glycerol 3,5 Sorbitol 0.2 Sodium citrate 1,0 Sodium chloride 0.6 Lemon acid 0.5 Distilled water Up to 100

Example 14

For the manufacture of the shell used a pre-prepared solution containing, by weight. %:

Agar agar 5 Glycerol 3,5 Sorbitol 0.2 Sodium citrate 1,0 Sodium chloride 1.7 Lemon acid 0.5 Distilled water Up to 100

Example 15

For the manufacture of the shell used a pre-prepared solution containing, by weight. %:

Agar agar 6 Glycerol 2 Sodium citrate 0.8 Lemon acid 0.01 Distilled water Up to 100

Example 16

For the manufacture of the shell used a pre-prepared solution containing, by weight. %:

Agar agar 6 Glycerol 2 Sorbitol 0.5 Sodium citrate 2.0 Sodium chloride 1.7 Lemon acid 0.01 Distilled water Up to 100

Example 17

For the manufacture of the shell used a pre-prepared solution containing, by weight. %:

Agar agar 6 Glycerol 6 Sorbitol 0.5 Sodium citrate 2.0 Sodium chloride 0.6 Lemon acid 0.7 Distilled water Up to 100

Example 18

For the manufacture of the shell used a pre-prepared solution containing, by weight. %:

Agar agar 6 Glycerol 6 Sodium citrate 2.0 Lemon acid 0.7 Distilled water Up to 100

Example 19

For the manufacture of the shell used a pre-prepared solution containing, by weight. %:

Agar agar 6 Glycerol 4,5 Sorbitol 0.2 Sodium citrate 1,0 Lemon acid 0.5 Distilled water Up to 100

Example 20

For the manufacture of the shell used a pre-prepared solution containing, by weight. %:

Agar agar 6 Glycerol 4,5 Sorbitol 0.2 Sodium citrate 1,0 Sodium chloride 0.6 Lemon acid 0.5 Distilled water Up to 100

Example 21

For the manufacture of the shell used a pre-prepared solution containing, by weight. %:

Agar agar 6 Glycerol 4,5 Sorbitol 0.2 Sodium citrate 1,0 Sodium chloride 1.7 Lemon acid 0.5 Distilled water Up to 100

Example 22

To prepare the capsule shell, compositions were used similarly to examples 1-21, but the capsule shell additionally contains zinc lactate or zinc sulfate in an amount of 0.05-1.5%.

Example 23

For the preparation of capsule shells, compositions were used similarly to examples 1-21, but the capsule shell additionally contains plant extracts: licorice extract 0.01%; Rhodiola rosea extract 0.1%.

Example 24

As a fat-soluble BAS, the core of the capsule may contain oily solutions of fat-soluble vitamins, such as vitamins A 0.01 to 20 wt. %, or vitamin E 0.1-50 wt. %, or vitamin D 0.01-20 wt. %, or vitamin K1 0.01-0.1 wt. %, or vitamin F (polyunsaturated fatty acids omega-3 and omega-6) 0.1-100 wt. %, or carotenoids (provitamin A or lycopene or astaxanthin or lutein or zeaxanthin or a mixture thereof) 0.01-20 wt. %, or coenzyme Q10 0.5-20 wt. %, or fish oil 0.1-100 wt. %, or selenoxanthene (selexen) 0.01-0.08 wt. %, or non-steroidal anti-inflammatory drugs (ibuprofen or ketoprofen) 5-70 wt. %, or a mixture of poly (dimethylsiloxane) and silicon dioxide 4-70 wt. %, or fatty oils of 0.1-100 wt. %, or lipid extracts from plant and / or animal raw materials 0.1-99.9 wt. %, or mixtures thereof, etc.

Example 25

Microscopic analysis of capsule shells

Microscopic analysis of the shells of soft gelatin and soft agar capsules was performed using an Axio Scope A1 microscope, Carl Zeiss, magnification 10x. The films were evaluated using the Axiovs 40 V 4.8.1.0 program.

For soft gelatin capsules, a shell thickness of 200 ± 21 μm was established. The shell thickness of the soft agar capsules was 50 ± 4 μm (Fig. 1).

Example 26

Analysis of the stability of the soft capsule shell under the influence of moisture

The effect of humidity on the stability of soft capsules based on agar-agar and gelatin polymers was studied for 28 days at a relative air humidity (RH) of 100% and a temperature of 18-25 ° C. The weight gain of the samples was controlled.

The rate of weight gain in the samples of soft gelatin and agar capsules was different (Fig. 2.). The mass growth rate in the sample of soft gelatin capsules exceeded the mass growth rate of soft agar capsules by 1.5 times (0.14% / hour compared to 0.09% / hour).

All samples changed appearance on day 4 (144 hours) of the experiment. On the 12th day of the experiment, samples of soft gelatin capsules were destroyed and overgrown with microorganisms. Samples of soft agar capsules at the end of the experiment on day 26 still contained an indestructible shell.

The destruction of soft capsules based on agar-agar polymer occurred on days 28-30.

Thus, on the basis of studying the stability of the shell of soft capsules under the influence of air humidity, it can be concluded that capsules based on the agar-agar polymer are 2.5-3 times more stable than gelatin capsules. We established the negative effect that increased air humidity has on the appearance, destructibility, and also microbial contamination of gelatin capsules, which necessitates the protection of the capsule from atmospheric air. As a rule, such problems are solved by the special storage conditions of the preparations in the form of soft gelatin capsules.

It should be noted that the effect of increased humidity on the stability of soft capsules makes it preferable to use agar-agar polymer for further studies.

Example 27

Biopharmaceutical evaluation of soft capsules based on agar-agar polymer

Received capsules, for the manufacture of the shell which used a pre-prepared solution containing, by weight. %: agar-agar - 4, glycerin - 2, distilled water - up to 100 (capsules with a shell of composition A)

Disintegration of the capsules was studied in accordance with the requirements of the Global Fund XI, vol. 2, p. 144 and EP 7.0, p. 708 for soft capsules on a laboratory identifier for disintegration process at 37 ° C.

It was found that capsules with a shell based on agar-agar composition A disintegrated in water within 20 minutes. The capsules of example 6 did not disintegrate within 30 minutes in water and 0.1 m hydrochloric acid.

In this regard, the disintegration of the capsules of example 6 was determined under the conditions of the disintegration test for enteric capsules (EP 7.0, p. 708). The test was carried out for 1 hour in 0.1 m hydrochloric acid, after which the capsules were washed with water, examined for damage, and the disintegration test was continued in a solution of phosphate buffer pH 6.8 using plastic discs.

The disintegration time of the capsules of Example 6 was no more than 5 minutes in a solution of phosphate buffer at 37 ° C, which corresponds to the requirements of GF XI, no. 2, p. 144 and EP 7.0, p. 708 for enteric capsules.

In accordance with EP 7.0, this test is sufficient for biopharmaceutical evaluation of enteric capsules containing lipophilic solutions of active substances as filler. Similar results were obtained for capsules prepared according to examples 1-5 and 7-24. The obtained results make it possible to recommend soft capsules based on agar-agar for encapsulating lipophilic substances, protecting substances from the acidic environment of the stomach, and ensuring the release of active substances in the intestine, which is most preferred for lipophilic substances.

The created shells of soft capsules based on the agar-agar polymer with the addition of auxiliary water-soluble components to provide the required structural and mechanical properties of the capsule shell - viscosity, fluidity, strength, disintegration in the intestines have a swelling biodegradable shell and contain both fat-soluble and water-soluble biologically active substances, can be easily obtained and used in medicine, in functional nutrition, in cosmetics. In addition, the use of capsules based on agar-agar will enrich the diet with dietary fiber.

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Claims (17)

1. A capsule with an enteric coating, obtained on the basis of agar-agar polysaccharide and substances that improve structural-mechanical and biopharmaceutical properties, and filled with oil solutions of fat-soluble vitamins, and / or oil extracts from plant materials, and / or fatty oils, and / or mixtures thereof, moreover, as a substance providing optimal structural-mechanical and biopharmaceutical properties, the capsule shell contains 0.1-5 wt.% sodium citrate and 0.01-2 wt.% citric acid, as well as 1-10 wt.% glycerin and / or 0.1-1 wt.% Sorbitol. 2. The capsule according to claim 1, characterized in that it contains an agar-agar polysaccharide in an amount of 1-10%. 3. The capsule according to claim 1, characterized in that, to increase the strength, the capsule shell may contain a sodium chloride salt in a concentration of 1-3 wt.%. 4. The capsule according to claim 1, in which the shell thickness is 3-4 times thinner than the shell of soft gelatin capsules. 5. The capsule according to claim 1, the stability of which at high humidity (RH = 100%) is 2.5-3 times higher than the stability of soft gelatin capsules. 6. The capsule according to claim 1, the disintegration of which, under the conditions of the disintegration test for enteric capsules, in a solution of phosphate buffer is not more than 5 minutes at 37 ° C. 7. The capsule according to claim 1, in which the moisture content of the shell is about 10-15%. 8. The capsule according to claim 1, characterized in that the composition of the shell further comprises water-soluble biologically active substances: trace elements and / or water-soluble plant extracts. 9. The capsule according to claim 8, in which zinc lactate or zinc sulfate is included in the shell as a water-soluble biologically active substance. 10. The capsule according to claim 8, in which, as a water-soluble plant extract, a dry licorice extract or a dry extract of Rhodiola rosea is included in the composition of the shell. 11. The capsule according to any one of paragraphs. 1-8, in which, as a fat-soluble biologically active substance, oil solutions of fat-soluble vitamins, such as vitamins A, 0.01-20 wt.%, And / or vitamin E 0.1-50 wt.%, Are included in the composition of the capsule core, and / or vitamin D 0.01-20 wt.%, and / or vitamin K1 0.01-0.1 wt.%, and / or vitamin F (polyunsaturated fatty acids omega-3 and omega-6) 0.1- 100 wt.%, And / or carotenoids (provitamin A or lycopene or astaxanthin or lutein or zeaxanthin or mixtures thereof) 0.01-20 wt.%, And / or coenzyme Q10 0.5-20 wt.%, And / or fish oil 0.1-100 wt.%, and / or selenoxanthene (selexen) 0.01-0.08 wt.%, and / or nester offensive anti-inflammatory drugs (ibuprofen or ketoprofen or others) 5-70 wt.%, and / or a mixture of poly (dimethylsiloxane) and silicon dioxide 4-70 wt.%, and / or fatty oils of 0.1-100 wt.%, and / or lipid extracts from plant and / or animal raw materials 0.1-99.9 wt.% or mixtures thereof, etc. 12. The capsule of claim 1, further comprising antioxidants, preservatives, flavorings, sweeteners, and colorants in the outer shell and / or core. 13. The method of preparing the solution for obtaining the capsule shell according to claim 1, wherein substances that improve the structural-mechanical and biopharmaceutical properties are added to water, mixed until dissolved, then agar-agar is added, left to swell at 15-40 ° C at 0 , 1-10 hours, after which the resulting mixture is stirred at a temperature of 70-99 ° C until the mixture becomes homogeneous and transparent. 14. The method according to p. 13, in which glycerol, sorbitol, sodium citrate, citric acid are used as substances that improve the structural-mechanical and biopharmaceutical properties. 15. The method of preparing the solution to obtain the capsule shell according to claim 13, in which sodium chloride is dissolved in water before adding the agar-agar. 16. The method of preparing capsules according to claim 1, in which a solution to obtain a capsule shell prepared by the method according to claim 13, is supplied to the capsule unit where they are molded and simultaneously filled with fat-soluble biologically active substances at a temperature of 70-99 ° C; the encapsulation rate of 1-20 capsules per second, the temperature of the coolant 3-15 ° C. 17. A method of increasing the strength of the capsule shell according to claim 1 by holding the capsules in ethanol, preferably in 95% ethanol, for 0.1-10 minutes.

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