WO2022211646A1

WO2022211646A1 - Globule comprising cetraria islandica thallus extract and the method of its preparation

Info

Publication number: WO2022211646A1
Application number: PCT/PL2021/050020
Authority: WO
Inventors: Lech LUCZAK; Marta BIALKOWSKA; Jacek FRANASIK; Kamil ZARLOK
Original assignee: Master Pharm S.A.
Priority date: 2021-03-30
Filing date: 2021-03-30
Publication date: 2022-10-06

Abstract

A method of obtaining the globule containing Cetraria Islandica thallus extract comprising the following steps: heating the water, adding galacto-oligosaccharides to the water and mixing until completely dissolved, then adding the Cetraria Islandica thallus extract to the solution and mixing until completely dissolved, then pH adjusting agent is added to the solution thus obtained and stirred until completely dissolved. Separately, cocoa butter is heated to 35-40°C, when the cocoa butter is completely melted, the stirring speed is increased to 700-800 rps and the previously obtained aqueous solution of galacto-oligosaccharides, Cetraria Islandica thallus extract and the pH regulating agent at a temperature of 35-40°C are added, wherein the ratio of water to cocoa butter is not less than 1: 6.58 by weight, the resulting emulsion is cooled to 25°C and poured into the form of globules. Vaginal globule containing fat 73.1% by weight, water 11.1% by weight, galactooligosaccharides 8.3% by weight, Cetraria Islandica thallus extract 3.3% by weight and pH adjusting agent 4.2% by weight.

Description

Globule comprising Cetraria islandica thallus extract and method of its preparation

The invention relates to vaginal globule comprising Cetraria islandica thallus extract and a method of its preparation

Cetraria islandica, also known as the Icelandic lichen, Icelandic crottle, Icelandic lungwort - is a lichen that occurs in the continents of the northern hemisphere and is very often used for medicinal purposes. Icelandic crottle comprises numerous acids, including approx. 2 percent of cetraric acid, which has bacteriostatic properties and stimulates intestinal peristalsis. Silicic acid and protolice steric acid are valuable in the lichen; the latter acts on the bacterium Helicobacter pylori, which is pathogenic for humans and responsible for the development of gastric and duodenal ulcers. It also comrpisies hemicelluloses, carbohydrates, mucilages, ash, minerals and vitamins.

Cetraria islandica is used in tuberculosis, gastritis, peptic ulcer disease and lung disease.

It has antitussive, anti-inflammatory, expectorant, strengthening and antiperspirant properties. Detoxifies. It will help soothe shattered nerves (has a calming effect). It has a protective and soothing effect on the mucosa of the throat, vocal cords and larynx, therefore it is recommended as a medicine in diseases of the upper respiratory tract. Increases saliva secretion. When given in high doses, it can stop vomiting. It is a natural remedy for seasickness and motion sickness.

It has a healing effect in skin diseases. Regular use of Icelandic lichen inhibits the excessive production of sebum, therefore masks or decoctions of this species have anti-acne and cleansing properties. Rinses with its use can also help with damaged hair.

European patent application No. EP1871340 A1 discloses a liquid pharmaceutical preparation which comprisies a combination of Icelandic moss and mallow, optionally with at least one zinc compound, in particular at least one zinc salt, and a pharmaceutically acceptable carrier - for the prophylactic and / or therapeutic treatment of various diseases, especially cough and cough irritations, especially dry cough irritations, irritation of the mucous membranes and damage to the mucosa in the mouth and throat, - drying of the mucosa in the area of the mouth and throat, hoarseness and bronchitis and bronchial asthma. In turn, the publication of the German utility model DE202005009181 U1 discloses a pharmaceutical preparation in liquid form, used to alleviate and suppress the symptoms of cough. The preparation comprisies a combination of an extract of Icelandic lichen ( Cetraria islandica ) and / or mallow ( Malva sylvestris L. A Malva neglecta Wallr.) In combination with a non-toxic carrier that can also be used in combination with zinc compounds, preferably zinc gluconate or zinc sulphate in% from 0.001 to 1 wt.%.

In turn, International Patent Application Publication No. W02006032364 A1 discloses a pharmaceutical composition in the form of a lozenge, in particular for the topical treatment of inflammatory diseases of the oral cavity and pharynx, comprising a combination of at least one mucilaginous drug and / or an extract thereof, in particular, Icelandic moss ( Cetraria islandica) and / or marshmallow {Althea officinalis L.) with at least one local anaesthetic. Also EP2617412 A1 describes the composition as comprising at least one mucilaginous drug and / or an extract thereof and polidocanol as a local anaesthetic.

European Patent Application Publication No. EP2293805 A1 discloses a pharmaceutical composition in the form of a lozenge dosage, particularly for the topical treatment of inflammatory diseases of the mouth and throat, cough and rhinitis of the upper respiratory tract, the composition being a combination of at least one first active ingredient which comprises at least one tanning drug and / or an extract thereof, and at least one second active ingredient component which comprises at least one mucilaginous material of the drug and / or its extract.

Formulations comprising Cetraria islandica disclosed in the prior art do not comprise any guidance on the composition of vaginal globules comprising this active ingredient, or on the method of preparation of such globules. Cetraria islandica thallus extract is a natural polymer that significantly changes the properties of the components of vaginal globules, and therefore it was necessary to develop an appropriate composition of the ingredients of this type of globules and the method of their preparation.

The aim of the invention was to develop a vaginal globule formulation and a method of its preparation which would guarantee the globules maintaining the appropriate structure at room temperature and in which the active ingredients would not sediment. Additionally, it was desired to develop such a globule formulation and method of preparation in which the ratio of the aqueous to the lipid phase would be as high as possible while at the same time not delaminating. It was also important to select the pH adjusting agent to suitably regulate the pH of the globule and to make this factor convenient for use in the preparation of the globule. The objective was also to develop such a composition of the globule that would guarantee a prolonged release time of active substances. The essence of the invention is a method of obtaining a globule comprising an extract of the thallus of Cetraria islandica, comprising the following steps: a) the water is heated to 40°C and galacto-oligosaccharides are added to the water, in particular in a proportion of 1: 0.75 by weight and stirred until completely dissolved, then the extract of Cetraria Islandica thallus, especially in a proportion of 1 : 0.3 by weight, is added to the solution thus obtained and stirred until completely dissolved, then a pH adjusting agent is added to the solution thus obtained, in particular in a proportion of 1: 0.38 by weight and stirred until completely dissolved, b) the fat is heated separately to a temperature of 40°C; c) when the fat is completely melted, the stirring speed is increased to 700-800 rps and the aqueous solution of galacto-oligosaccharides obtained in step c), Cetraria islandica thallus extract and the acid pH adjusting agent at 40°C are added, wherein the water to fat ratio is not less than 1: 6.58 by weight, d) the emulsion thus obtained is cooled to 25°C and poured into the form of globules.

Preferably, in the process according to the invention, the fat used in steps b) and c) is a fat selected from the group: shea butter, palm oil, lanolin, mango butter, egg butter or especially cocoa butter. It is particularly preferred that the ratio of water to cocoa butter is from 1 : 5.7 to 1 : 6.6% by weight.

Preferably, an acid selected from the group of lactic acid, citric acid, malic acid, malonic acid or especially 1-ascorbic acid is used as the pH adjusting agent in the process according to the invention.

Preferably, in the process according to the invention, the temperature of steps a) to c) is 40°C.

Preferably, in the process according to the invention, the mixing speed in steps a) to c) is 200 rps.

According to another aspect, the invention relates to a vaginal globule comprising: fat 73.1% by weight, water ll.l% by weight, galactooligosaccharides 8.3%by weight, Cetraria Islandica thallus extract 3.3% by weight and pH adjusting agent 4.2% by weight.

Preferably, in the globule according to the invention, the fat selected from the group: shea butter, palm oil, lanolin, mango butter, egg butter or especially cocoa butter.

Preferably, the pH adjusting agent in the globule according to the invention is an acid selected from the group: lactic acid, citric acid, malic acid, malonic acid or especially 1-ascorbic acid. It is more preferable when the globules comprising Cetraria Islandica thallus consist of: cocoabutter 73.1% by weight, water 11.1% by weight, galactooligosaccharides 8.3% by weight, Cetraria Islandica thallus extract 3.3% by weight and L-ascorbic acid 4.2% by weight.

The subject matter of the invention is presented in non-limiting embodiments.

Embodiment 1. Testing various methods of obtaining globules comprising Cetraria Islandica thallus extract

In experiment A, a standard globule based on glycerin was prepared. For this purpose, the appropriate 60 g of water and 280 g of glycerin (99.7%, Przcdsicbiorstwo Przemyslowo Handlowe "STNADARD" Sp. z o.o.) were weighed in a beaker, then 60 g of gelatin were added. The whole was heated on a magnetic stirrer to a temperature of 100°C, with constant stirring. After a clear mixture was obtained, cooling was commenced while stirring.

At a temperature of about 50°C, it was poured into moulds, placed in a refrigerator, and 10 globules were obtained. The composition of the substrate is appropriate. The globule retains its shape after taking it out of the mould. The composition of the globules obtained in experiment A compared to other experiments is presented in Table 1.

In experiment B the active ingredients were added to the composition of experiment A. For this purpose, corresponding 55.2 g of water and 257.6 g of glycerol were weighed in a beaker. Then, the mixture was heated on a magnetic stirrer to a temperature of 100°C, with constant stirring. All active substances and preservative were added, i.e. 65 g of galacto-oligosaccharides (Vivinal GOS Powder, DOMO), 26 g of Cetraria Islandica thallus extract (DER = 4: 1, greyish- brown powder, Greenvit), 32.5 g of F-finic acid and 2.5 g of potassium sorbate (potassium salt of sorbic acid, Brenntag Polska). After a clear mixture was obtained, 55.2 g of gelatin was added. Cooling was then commenced while stirring. At a temperature of about 50°C, it was poured into moulds, placed in a refrigerator, and 10 globules were obtained. It was observed that there is too much solids in the obtained globules and the globules do not solidify after being placed in the refrigerator. The composition of the globules obtained in experiment B compared to other experiments is presented in Table 1.

In experiment C, the same ingredients were used as in experiment B, only the order of adding the ingredients was changed. 55.2 g of water and 257.6 g of glycerin were weighed in a beaker, then 55.2 g of gelatin was added. The whole was heated on a magnetic stirrer to a temperature of 100°C, with constant stirring. After a clear mixture was obtained, cooling was commenced while stirring. The active ingredients and preservative were added at a temperature of about 80°C, i.e. 65 g of galacto-oligosaccharides, 26 g of Cetraria Islandica thallus extract (DER = 4: 1), 32.5 g of L-ascorbic acid and 2.5 g of potassium sorbate. At a temperature of about 50°C, it was poured into moulds, placed in a refrigerator, and 10 globules were obtained. In this case too, too much solids were observed. The globule did not solidify after being placed in the refrigerator. In addition, the substances dissolve poorly when the gelatin has previously been dissolved. The composition of the globules obtained in experiment C compared to other experiments is presented in Table 1.

In experiment D, 344.6 g of cocoa butter was weighed in a beaker. It was heated to 40°C for complete melting. When the whole was melted, the active substances were added, i.e. 16.2 g of galacto-oligosaccharides, 13 g of Cetraria Islandica thallus extract (DER = 4: 1) and 16.2 g of L-ascorbic acid. The mixture was then cooled. At a temperature of about 25°C, it was poured into mould, placed in a refrigerator, and 10 globules were obtained. The globules obtained as a result of this experiment had the appropriate structure, however, the active substances were sedimented. The composition of the globules obtained in experiment D compared to other experiments is presented in Table 1.

In experiment E, 33.2 g of water was weighed in a beaker and heated to 40°C. Then 25 g of galacto-oligosaccharides were added to water and mixed until completely dissolved.

The dissolution time of the galacto-oligosaccharides was 30 min. Then 10 g of Cetraria Islandica thallus extract (DER = 4: 1) was added to the water and mixed until completely dissolved. The dissolution time of the extract was 45 min. Then 12.5 g of L-ascorbic acid was added to water and stirred until completely dissolved. The dissolution time of L-ascorbic acid was 10 min. The best process efficiency was achieved with a stirring speed of 200 rps. Then,

219 g of cocoa butter was weighed into a beaker and heated to 40°C until it was completely melted. When all of the cocoa butter had melted, the previously prepared water at 40 ° C with the dissolved active substances were added with very vigorous stirring at a stirring speed of 700- 800 rps. The mixing took 5 - 10 minutes. In this way, it was possible to keep the emulsion stable. The mixture was then cooled. At a temperature of 25°C, it was poured into mould and 10 globules were obtained. The obtained globules had the appropriate structure - a homogeneous light brown substance without any signs of delamination. At room temperature of 15-25 ° C, the globules froze and the active substances did not sediment. The composition of the globules obtained in experiment E compared to other experiments is presented in Table 1.

In experiment F, an appropriate 246.1 g of cocoa butter was weighed into a beaker, which was then heated to 40°C to completely melt. In the second beaker, 43.2 g of water was weighed and active substances were added, each additional substance was added after the previous one had completely dissolved, i.e. 32.5 g of galacto-oligosaccharides, 13 g of Cetraria Islandica thallus extract (DER = 4: 1) and 16.2 g L-ascorbic acid. When all of the cocoa butter had melted, the active substances dissolved in water were added with very vigorous stirring. The emulsion was kept stable. Part of the emulsion was taken and 3.9 g of the dye zinc oxide was thoroughly mixed. The resulting mixture was re-added to the rest of the emulsion and stirred for a few minutes. The mixture was then cooled. At a temperature of about 25°C, it was poured into mould and 10 globules were obtained. As a result, globules with an appropriate structure and much brighter colour than in the previous tests were obtained. At room temperature, the globules froze, the active substances did not sediment, however, the dye sedimented.

The composition of the globules obtained in experiment F compared to other experiments is presented in Table 1.

Table 1. Composition of the globule produced in individual experiments

As a result of a series of experiments, it was unexpectedly found that obtaining globules with an appropriate structure was possible only when the method according to experiments E and F was carried out. In experiment F, the structure of the globule was appropriate and the active ingredients did not sediment, but the additional component of the dye composition - zinc oxide, unfortunately sedimented. It was observed that in the globules obtained in the D-F experiments with the use of a fatty medium, the release process of active substances was slower compared to the use of the hydrophilic medium in the B-C experiments.

Embodiment 2 Aqueous phase optimization

The optimization of the aqueous -to-fat phase for the water-cocoa butter mixture was carried out as follows: cocoa butter was melted at 40°C, with strong mechanical stirring (200 to 300 rpm), distilled water heated to 40°C was added for 2 minutes. The mixture was left overnight at 20°C. The limit for the maximum water content in cocoa butter is 13 g of water per 87 g of cocoa butter (1:6.6).

Table 2. The form of the mixture depending on the amount of water to fat phase

Embodiment 3 Comparison of the formation of water emulsion with different fats

For the compositions of Example 1 of Experiment E, additional tests were carried out with various types of fats to see if the cocoa butter used could be substituted. A variety of other fats were tested (Table 3) which have a melting point of around 40°C. It has turned out that different fats can be used in the process of the invention, however cocoa butter has a sufficient emulsification level with water of more than 8%, high room temperature hardness and chemical stability.

Table 3. Comparison of emulsion with different fat types

Embodiment 4 Selection of pH adjusting agents

The pH adjusting agents were also optimized. Additional tests were carried out on the compositions of Example 1, Experiment E with various organic acids to regulate the pH of the globule (Table 4). Satisfactory results were obtained in all variants, but L-ascorbic acid turned out to be the best agent regulating the pH, because it is characterized by good water solubility, has an acceptable pH and antioxidant properties, and shows no chemical influence on other active substances contained in the globule.

Table 4. Comparison of pH adjusting agents

For L-ascorbic acid, an additional beneficial effect related to its antioxidant properties was observed.

Claims

1. A method of obtaining a globule comprising an extract of the thallus of Cetraria islandica, comprising the following steps: a) the water is heated to about 40°C, galacto-oligosaccharides are added to the water, especially in a proportion of 1: 1.33 by weight and stirred until completely dissolved, then the extract of Cetraria Islandica thallus is added to the solution thus obtained, in particular in a proportion of 1: 3.33 by weight and stirred until completely dissolved, and then a pH adjusting agent is added to the solution thus obtained, especially in a proportion of 1: 2.6 by weight and stirred until completely dissolved, b) the fat is heated separately to a temperature of about 40°C; c) when the fat is completely melted, the stirring speed is increased to 700-800 rps and the aqueous solution of galacto-oligosaccharides obtained in step c), Cetraria islandica thallus extract and the acid pH adjusting agent at 40°C are added, wherein the water to fat ratio is not less than 1: 6.58 by weight, d) the emulsion thus obtained is cooled to 25 °C and poured into the form of globules.

2. The method according to claim 1, wherein the fat selected from the following group is used as a fat: shea butter, palm oil, lanolin, mango butter, egg butter or especially cocoa butter.

3. The method according to claim 2, wherein the ratio of water to cocoa butter is from 1: 5.7 to 1: 6.6% by weight.

4. The method according to claim 1, wherein acid selected from the group of: lactic acid, citric acid, malic acid, malonic acid or especially 1-ascorbic acid is used as the pH adjusting agent.

5. The method according to claim 1, wherein the temperature of steps a) to c) is 40°C.

6. The method according to claim 1, wherein the mixing speed in steps a) to c) is 200 rps.

7. A vaginal globule comprising fat 73.1 % by weight, water 11.1 % by weight, galactooligosaccharides 8.3% by weight, Cetraria Islandica thallus extract 3.3% by weight and pH adjusting agent 4.2% by weight.

8. The clobule according to claim 7, wherein the fat selected from the following group is used as a fat: shea butter, palm oil, lanolin, mango butter, egg butter or especially cocoa butter.

9. The clobule according to claim 7, wherein pH adjusting agents is acid selected from the group of: lactic acid, citric acid, malic acid, malonic acid or especially L-ascorbic acid is used as the pH adjusting agent.

10. The clobule according to claim from 7 to 9, wherein it consists of cocoa butter 73.1% by weight, water 11.1% by weight, galactooligosaccharides 8.3% by weight, Cetraria Islandica thallus extract 3.3% by weight and L-ascorbic acid 4.2% by weight.