RU2405542C2 - Extruded soft capsule, method to prepare capsule-filling solution, capsule manufacture method and method to raise density of agar coating - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical and pharmaceutical industry, notably to development of capsule with turgescent coating made of agar-agar with or without addition of water-soluble biologically active compounds, filled with oily solutions of oil-soluble vitamins and/or herbal oily extracts and/or fatty oils or fatty oils mixtures. Solution for encapsulation is prepared in the following manner: plastifier is added to water, stirred till complete dissolution, then agar-agar is added and left to turgesce at 15-40°C during 0.1-10 hours, preferably about 0.5-2 hours; then obtained mixture is stirred at 70-99°C, preferably at 80-98°C, most preferably at 95°C till mixture will become homogenous and transparent. Then capsules are manufactured as follows: solution is delivered in extruder which extrudes capsules at 77-99°C, preferably at 82-90°C, most preferably at 86°C; extruding rate is 1-10 capsules per second, preferably 3-6 capsules per second, cooling fluid's temperature is 3-15°C. Higher density of capsule agar covering is achieved by subsequent exposure to solution of polyol during 0.1-30 minutes, preferably 0.5 minutes, then to ethanol, preferably 95%, during 1-20 minutes, preferably 5 minutes.

EFFECT: capsules are resistant to temperature and humidity gradients, free of animal proteins thus excluding prionic infections.

16 cl, 27 ex

Description

The invention relates to the food, pharmaceutical and cosmetic industries and relates to encapsulated biologically active food additives, drugs and skin care products, based on extrusion technology for creating gelatin capsule shells with swelling properties, while filling them with lipophilic solvent-based contents and inclusion of water-soluble biologically active substances (BAS) in the shell material, and fat-soluble in the core.

Soft capsules made from gelatin as the main shell material are widely distributed in various fields: in functional nutrition as a source of vitamins, squalene, coenzyme Q10, etc .; in medicine, as preparations, for example, nitroglycerin, validol, and the like; in cosmetics as bath oils, etc.

The advantage of soft gelatin capsules is that there is a simultaneous process of forming the shell, filling with contents and clogging the finished capsule. Preparations in soft gelatin capsules have several advantages over solid dosage forms:

1. Easy to dose.

2. The process is strictly automated and controlled.

3. Prevention of contamination of the finished product with related impurities.

4. Protection against contact with air.

5. Ease of use by patients.

6. High bioavailability.

Known inventions for creating soft capsules with a shell based on starch (1) and hydrolyzed starch (2). The disadvantage of these inventions is that in the production of starch-based capsules, it is necessary to additionally include a gelling agent, for example, carrageenan or guar gum, in the shell, that is, additional costs for auxiliary substances are required, which leads to higher cost of the technology and an increase in the cost of the final product. Since starch is hygroscopic and has good swelling properties, capsules based on it are unstable at a humidity of more than 25% and a temperature of more than 40 ° C, and they are also a good nutrient medium for microorganisms (3).

There are studies on the creation of capsules based on cellulose and its derivatives: hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxyethyl cellulose, methyl cellulose, etc. (4, 5). Derivatives of cellulose are mainly used to create hard shells of capsules, or are used in conjunction with other hydrocolloid-forming components to give hardness to the shell.

A known technology for producing soft capsules having an agar-based shell (6). Capsules with an agar-based shell are prepared by the conventional drop (extrusion) method. The disadvantage of these capsules is that their shell, without increasing its density, easily collapses from mechanical influences, and thus there are difficulties in the production of capsules, since the washing process from process oil according to the drip method used by the authors is difficult and is accompanied by large losses, which is not economically feasible . There are also difficulties 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 above method does not indicate the parameters of the technological process for producing soft capsules based on agar, and in this regard, it is impossible to evaluate the advantages of agar capsule technology.

To add strength to the shell, various sugars are added to its composition: monosugar (fructose, glucose), disaccharide (sucrose), polysaccharides (pullulan), sugar alcohols (sorbitol, mannitol, xylitol) (2). The addition of various sugars to the non-gelatin shell results in additional costs for excipients and thereby to higher cost of technology, and an increase in the cost of the final product.

The composition of the capsule shell sometimes includes auxiliary water-soluble components to provide the required physical and mechanical properties of the capsule shell - plasticity, strength, accelerated disintegration in the digestive tract and others (7). However, these water-soluble additives are not biologically active substances selected from the point of view of pharmacological feasibility to ensure the complex effect of the encapsulated preparation.

Closest to the proposed invention is a soft gelatin 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 drug in general (8).

The disadvantage is that the capsule shell is made of gelatin. With gelatin, it is possible to transfer prions - small infectious particles that are resistant to inactivating effects that can modify nucleic acids and cause Creutzfeldt-Jakob disease, transmissible spongiform encephalopathies; gelatin capsules are not suitable for vegetarians and people who eat halal and kosher food; at a temperature of more than 40 ° C or at a humidity of more than 75%, the gelatin shell is destroyed.

The present invention is the creation of soft capsules having a swelling agar shell, so that it is not inferior in strength to the gelatin shell, has a minimum amount of auxiliary substances, provides the possibility of additional inclusion of water-soluble biologically active substances, and was also suitable not only for sublingual, but also for oral administration.

The problem is solved in that the known soft capsule consists of a shell of gelatin containing at least one biologically active substance and a solution of at least one biologically active substance in oil (8), according to the invention, they are pre-mixed for a swellable shell 0 , 1-15% of a plasticizer with water, add, if necessary, water-soluble biologically active substances and 0.1-15% of a thickener; soft agar capsules are obtained by extrusion with the simultaneous filling of them with oil solutions of fat-soluble vitamins and / or oil extracts from plant materials and / or vegetable, fish oil and / or their mixtures in a capsule unit (9) at a temperature of 80-95 ° С, speed encapsulation of 1-10 capsules per second, the temperature of the coolant 3-15 ° C, incubated in a solution of polyhydric alcohol for 0.1-30 minutes, and then in ethanol for 1-20 minutes and dried.

We have experimentally found that it is preferable to use 1-9% agar agar as a thickener, and 1-10% glycerol and / or sorbitol and / or polyethylene glycol is preferably used as a plasticizer. 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 stirred at a temperature of 70-99 ° C, preferably at a temperature 80-98 ° C, most preferably at 95 ° 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. For this, during the preparation of the solution for encapsulation, before adding the agar-agar, in water, preferably at a temperature of 40-60 ° C, trace elements, water-soluble plant extracts, preferably zinc lactate or zinc sulfate in an amount of 0.01-1.5% are dissolved or dry licorice extract or Rhodiola rosea extract in an amount of 0.01-0.2%. Dissolution is carried out until the mixture becomes homogeneous.

As a fat-soluble biologically active substance, the core of the capsule may contain oily solutions of fat-soluble vitamins, such as vitamins A 0.01-20 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 (omega-3 and omega-6 polyunsaturated fatty acids) 0.1-100 wt.% Or carotenoids (provitamin A or lycopene or astaxanthin or lutein or zeaxanthin or mixtures 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 fatty oils 0, 1-100 wt.% Or lipid extracts from plant materials 0.1 -99.9 wt.% Or mixtures thereof, etc.

Experimental studies conducted by the authors have shown that it is rational to obtain capsules on a capsulator installation where they are molded and filled by extrusion at a temperature of 77-99 ° C, preferably at 82-90 ° C, most preferably at 86 ° C. The encapsulation rate is 1-10 capsules per second, preferably 3-6 capsules per second. The temperature of the coolant is 3-15 ° C.

In the production of capsules, we found that the shell of agar capsules without changing its density easily changes shape and collapses from mechanical influences, difficulties arise in the process of washing capsules from process oil, as well as during packaging, transportation and storage of capsules. Therefore, it is necessary to increase the density of the agar shell of the capsules by sequentially exposing them in a solution of polyhydric alcohol, preferably sorbitol, for 0.1-30 minutes, preferably 0.5 minutes, followed by exposure in ethanol, preferably in 95% ethanol, for 1-20 minutes, preferably within 5 minutes. This technological technique allowed increasing the strength of the shell without adding auxiliary substances to its composition.

Spherical 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 the Pharmacopoeia of the USSR XI ed. and was no more than 20 minutes at 37 ° C.

Compared with the technology of soft gelatin capsules (8), the proposed method for producing agar capsules allows to reduce the time to obtain capsules, because there is no stage of capsule aging in the cold for 24 hours. Soft agar capsules are more durable and resistant to changes in temperature and humidity, compared with soft gelatin capsules, which positively affects their storage and transportation. In addition, the agar capsules do not contain animal protein, which positively affects the possibility of their use by vegetarians and adherents of some religious worldviews, and also prevents infection with prion infections.

In contrast to the known method for producing agar capsules (6) according to the invention, capsules with a strong agar shell less susceptible to mechanical stress were obtained, and thus there is no difficulty in their production, packaging, transportation and storage. This invention allows to reduce by 4-14 times the amount spent on the production of a thickener agar-agar shell and plasticizer, which is economically viable. Capsules are suitable not only for sublingual, but also for oral administration.

In addition, in this invention the parameters of the technological process for producing soft capsules based on agar-agar are indicated, and in this regard, it is possible to evaluate the advantages of this technology in comparison with previously known technologies.

Examples of capsules:

Example 1

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

Agar agar 3 Glycerol one Distilled water up to 100

Oil solutions of fat-soluble vitamins and / or oil extracts from plant materials and / or fatty oils were used as the core of the capsules.

Example 2

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

Agar agar 12 Glycerol 12 Distilled water up to 100

Oily solutions of fat-soluble vitamins and / or oil extracts from plant materials and / or fatty oils were used as the core (contents) of capsules.

Example 3

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

Agar agar 6 Glycerol four Distilled water up to 100

To prepare the core used a composition containing

rhizome oil extract with the roots of Valerian officinalis up to 100 wt.%.

Example 4

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

Agar agar 5 Glycerol 3 Dry licorice extract 0.1 Distilled water up to 100

Oily solutions of fat-soluble vitamins and / or oil extracts from plant materials and / or fatty oils were used as the core (contents) of capsules.

Example 5

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

Agar agar 10 Glycerol 10 Distilled water up to 100

To prepare the core used a composition containing, wt.%:

Alpha Tocopherol Acetate (Vitamin E) 5 Refined sunflower oil up to 100

Capsule disintegration time was 14 minutes.

Example 6

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

Agar agar 5 Glycerol 3 Zinc Lactate 0.01 Distilled water up to 100

To prepare a solution of the core used a composition containing, wt.%:

Alpha Tocopherol Acetate (Vitamin E) 0.5 Coenzyme Q10 10.0 Refined sunflower oil up to 100

Example 7

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

Agar agar 6 Glycerol four Zinc Lactate 0.1 Distilled water up to 100

To prepare the core used a composition containing, wt.%:

Alpha Tocopherol Acetate (Vitamin E) fifty Refined sunflower oil up to 100

Capsule disintegration time was 16 minutes.

Example 8

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

Agar agar 6 Glycerol four Zinc Lactate 0.1 Distilled water up to 100

To prepare the core used a composition containing, wt.%:

Alpha Tocopherol Acetate (Vitamin E) 0.18 Retinol palmitate (Vitamin A) 0.19 Beta Carotene (provitamin A) 0.18 Phytomenadion (Vitamin K1) 0.06 Rosemary oil 0.1 Refined sunflower oil up to 100

Capsule disintegration time was 13 minutes.

Example 9

For the preparation of capsules, compositions were used similarly to examples 6, 7, 8, but containing zinc sulfate instead of zinc lactate.

Example 10

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

Agar agar 9 Glycerol 8 Distilled water up to 100

To prepare the core, a composition containing fish oil up to 100 wt.% Was used. Capsule disintegration time was 16 minutes.

Example 11

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

Agar agar 3 Glycerol one Distilled water up to 100

To prepare the core used a composition containing, wt.%:

High oleic safflower oil up to 100

(source of polyunsaturated fatty acids Omega-3 and Omega-6)

Example 12

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

Agar agar four Glycerol four Distilled water up to 100

To prepare the core used a composition containing, wt.%:

Selenoxanthene (selexen) 0,03 (selenium) (0.007) Refined sunflower oil up to 100

Example 13

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

Agar agar 7 Glycerol 7 Distilled water up to 100

To prepare the core used a composition containing, wt.%:

Selenoxanthene (selexen) 0,03 (selenium) (0.007) Alpha Tocopherol Acetate (Vitamin E) 0.18 Refined sunflower oil up to 100

Example 14

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

Agar agar 3 Glycerol four Distilled water up to 100

To prepare the core used a composition containing, wt.%:

Selenoxanthene (selexen) 0.08 (selenium) (0.019) Refined sunflower oil up to 100

Example 15

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

Agar agar 9 Glycerol 9 Distilled water up to 100

To prepare the core used a composition containing, wt.%:

Lycopene 0.55 Rosemary oil 0.1 Refined sunflower oil up to 100

Example 16

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

Agar agar 9 Glycerol 9 Distilled water up to 100

To prepare the core used a composition containing, wt.%:

Astaxanthin 0.5 Rosemary oil 0.1 Refined sunflower oil up to 100

Example 17

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

Agar agar 2 Glycerol 7 Distilled water up to 100

To prepare the core used a composition containing, wt.%:

Lutein 1,5 Zeaxanthin 0.16 Selenoxanthene (selexen) 0,034 (selenium) (0.008) Rosemary oil 0.1 Refined sunflower oil up to 100

Example 18

For the preparation of capsules, compositions were used analogously to examples 10, 11, 12, 13, 14, 15, 16, 17, but the capsule shell additionally contains 0.01% zinc lactate.

Example 19

For the preparation of capsules, compositions were used analogously to examples 10, 11, 12, 13, 14, 15, 16, 17, but the capsule shell additionally contains 0.05% zinc lactate.

Example 20

For the preparation of capsules, compositions were used similarly to examples 10, 11, 12, 13, 14, 15, 16, 17, but the capsule shell additionally contains 0.1% zinc lactate.

Example 21

For the preparation of capsules, compositions were used similarly to examples 10, 11, 12, 13, 14, 15, 16, 17, but the capsule shell additionally contains zinc lactate 1.5%.

Example 22

For the preparation of capsules, compositions were used similarly to examples 10, 11, 12, 13, 14, 15, 16, 17, but the capsule shell additionally contains licorice extract 0.01%.

Example 23

For the preparation of capsules, compositions were used similarly to examples 10, 11, 12, 13, 14, 15, 16, 17, but the capsule shell additionally contains an extract of Rhodiola rosea 0.1%.

Example 24

For the preparation of capsules, compositions were used analogously to examples 18, 19, but containing zinc sulfate instead of zinc lactate.

Example 25

For the preparation of the kernel, compositions were used similarly to examples 5, 6, 7, 8, 12, 13, 14, 15, 16, 17, but containing instead of sunflower oil corn, or soybean, or rapeseed, or olive, or milk thistle, or amaranth, or railing, or evening primrose oil or a mixture thereof, etc.

Example 26

The capsules of example 3 were obtained in a capsule installation by extrusion at a temperature of 85 ± 1 ° C, the encapsulation rate of 5 capsules per second, the temperature of the coolant 10 ± 1 ° C, kept in a solution of mannitol for 1 minute, and then in ethyl alcohol, for 4 minutes and dried.

Spherical capsules were obtained having a smooth surface, without damage and visible air and mechanical inclusions, filled with a yellowish oily liquid. Capsule disintegration time was 17 minutes.

Example 27

The capsules of example 6 were obtained in a capsule installation by extrusion at a temperature of 87 ± 1 ° C, the encapsulation rate of 4 capsules per second, the temperature of the coolant was 9 ± 1 ° C, kept in sorbitol solution for 0.5 minutes, and then in ethanol , for 5 minutes and dried.

Spherical capsules were obtained having a smooth surface, without damage and visible air and mechanical inclusions, filled with a bright yellow oily liquid.

Using modern physicochemical methods of analysis, it was found that in the resulting preparation an accurate dosage of both fat-soluble biologically active substances (as part of the capsule core) and water-soluble biologically active substances as part of the capsule shell was provided. The capsule is suitable for oral use, disintegration time - 18 minutes.

Created soft extrusion capsules based on agar-agar, have a swelling biodegradable shell and contain a complex of both fat-soluble and water-soluble biologically active substances, can be easily obtained and used in functional nutrition, in medicine, in cosmetics. In addition, the use of capsules based on agar-agar will enrich the diet with dietary fiber.

Literature

1. Patent CA 2568822, 2007.

2. Patent EP 1447082, 2004.

3. Patent WO 03009832, 2003.

4. Application US 2007218127, 2007.

5. Patent EP 1029539, 2000.

6. Patent EP 0389700, 1990.

7. Patent RU 2102981, 1998.

8. Patent RU 2157192, 2000.

9. Patent RU 2109504, 1996.

Claims (16)

1. A capsule with a swelling shell made of 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 mixtures thereof. 2. The capsule according to claim 1, characterized in that, as a water-soluble biologically active substance, the shell may contain trace elements and / or water-soluble plant extracts. 3. The capsule according to claim 2, in which zinc lactate or zinc sulfate is included in the composition of the shell as a water-soluble biologically active substance. 4. The capsule according to claim 2, in which, as a water-soluble biologically active substance, a dry licorice extract or a dry extract of Rhodiola rosea is included in the composition of the shell. 5. The capsule according to any one of claims 1 to 4, in which, as a fat-soluble biologically active substance, oil solutions of fat-soluble vitamins, such as vitamins A 0.01-20 wt.% Or vitamin E 0.1-50 are included in the composition of the capsule core 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 mixtures 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 fatty oils 0.1-100 wt.%, or lipid extracts from plant materials 0.1-99.9 wt.%, or mixtures thereof, etc. 6. The capsule according to claim 1, in which the proportion of the shell by weight is about 4% of the weight of the entire fluid filling it. 7. The capsule according to any one of claims 1 to 4, having a substantially spherical shape and a diameter of up to 10 mm. 8. The capsule according to claim 1, in which the moisture content of the shell is about 13%. 9. The capsule according to claim 5, additionally containing in the outer shell and / or in the core antioxidants, preservatives, flavorings, sweeteners, colorants. 10. The method of preparing the encapsulation solution according to claim 1, 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 0, 5-2 hours, more preferably about 1 hour, after which the resulting mixture is stirred at a temperature of 70-99 ° C, preferably at a temperature of 80-98 ° C, most preferably at 95 ° C until the mixture becomes homogeneous and transparent. 11. The method of preparing the solution for encapsulation of claim 10, in which, before adding the agar-agar, trace elements, water-soluble plant extracts are dissolved in water. 12. The method of preparing the solution for encapsulation of claim 10, in which zinc lactate or zinc sulfate is dissolved in water in an amount of 0.01-1.5% before adding agar-agar. 13. The method according to any one of claims 10-12, in which glycerol is used as a plasticizer. 14. A method of preparing capsules in which the encapsulation solution of claim 10 is supplied to the capsule unit, where they are extruded at a temperature of 77-99 ° C, preferably at 82-90 ° C, most preferably at 86 ° C, the encapsulation rate 1-10 capsules per second, preferably 3-6 capsules per second, the temperature of the coolant is 3-15 ° C. 15. The method of increasing the density of the agar shell of the capsules by sequentially exposing the capsules in a solution of polyhydric alcohol for 0.1-30 minutes, preferably 0.5 minutes, followed by exposure in ethanol, preferably in 95% ethanol, for 1-20 minutes, preferably for 5 minutes 16. The method according to clause 15, in which sorbitol is used as the polyhydric alcohol.