CH647534A5 - CYCLODEXTRIN-CHAMOMILE INCLUSION COMPLEXES, METHOD FOR THE PRODUCTION OF THE COMPLEXES AND THE COMPLEXES CONTAINING THE COMPLEXES. - Google Patents

Description

The present invention relates to cyclodextrin-chamomile inclusion complexes, processes for their preparation and preparations containing the complexes.

Chamomile (Flores chamomillae) and the yarrow used in therapy (Achillea collina) and Roman chamomile (Anthemis nobilis) have long been known for their active ingredient and are used in therapy.

The flowers of the plants are used, whose decoction is effective internally in the case of intestinal inflammation, gastritis and bladder catarrh and in the case of conjunctivitis, maxillary sinus infection and inflammation of the ear canal as an external envelope. The camazulene contained in the chamomile essential oil releases histamine, activates the reticulo-endothelial system and speeds up the healing process of the persistent torpid-5-like inflammatory processes.

The chamomile drug can be used in two ways:

1) either an aqueous decoction (= chamomile tea) is prepared from the chamomile, which contains flavonoids, coumarins and aromatic and aromatic substances characteristic of the chamomile, but which only contains a small part of the pharmacologically active essential oil-terpene components,

2) Chamomile oil is made. The oil is not used immediately, it is added to ointments, creams, powders, i.e. generally to anti-inflammatory preparations. The oil is only

15 not very stable, the preparations containing the oil quickly lose their stability. The oil does not show the well-known camomile aroma either.

The important active ingredients of chamomile oil:

1- Bizabolol 20 Kamazulen Dicycloether Bizabolol-oxide I Bizabolol-oxide II Pharnezen 25 Herniarin

Another disadvantage of using the flower is that the active ingredient content is constantly reduced during storage and the drug is accompanied by an essential microbiological and also parasitic infection. 30 T he blue oil extracted from the flower is free from infection or contamination, but its stability is even less. The active substance content in the preparations containing blue oil can only be guaranteed for a short time. So the stabilization of the active ingredient is not solved with any commercially available preparation. 35 The commercially available chamomile preparations (in liquid or tableted form) have a completely different composition than natural chamomile, which contain only a small part of the original active ingredients and mainly decomposition products. The 40 products are reminiscent of chamomile just a short time after being sold, but chemical analysis can reveal significant differences.

A commercially available liquid product was analyzed by chromatography and a total of two undecomposed camomile oil components could be detected from the preparation six months after distribution. One component was Kamazulen, which is only 15-20% of the Kamazulene content of chamomile oil. However, it is also likely that the substance thought to be kamazulene is only azulene (artificially produced azulene). Traces of 1-bizabolol and a further two - presumably - decomposition products could still be detected from the chamomile drops. The product smells slightly burnt and is a brown alcoholic liquid.

A single flavone compound could be detected, but it could not be identified with any of the chamomile flavones.

Instant tea made from vaporized and dried chamomile tea was also analyzed. According to chromatographic analysis, the tea does not contain any of the volatile 60 oil components listed above. An unidentifiable decomposition product was detected with the specific reagent of the terpenes. The product contains a large number of flavones, which are presumably different glycosides of the Apigenin Fla-von.

65 With the help of the present invention, the active ingredient, the aromas and fragrances of the chamomile can be stabilized. According to the invention, inclusion complexes are produced which contain liquid active substances and aromas or fragrances in one

solid carrier: included cyclodextrin. The inclusion complexes enable easier treatment and the dosage can be made much more precise.

The cyclodextrins are closed rings consisting of glycopiranoses, the steric configuration of which can be characterized by a hydrophilic surface and a hydrophobic closed inner space. So when these cyclodextrins are converted into an aqueous solution with hydrophobic molecules, so-called inclusion complexes are formed. The molecules of the drug or flavoring agent that are included in the inclusion complex are largely protected from external effects (such as oxygen, heat, light, etc.). The active ingredients can thus be stabilized by complex formation and can be formulated directly using pharmaceutical-technological methods.

The present invention relates to cyclodextrin-camomile inclusion complexes which consist of cyclodextrin as guest molecules and of a camomile extract as enclosed molecules.

The inclusion complex contains an extract made from Flores chamomillae and / or Anthemis nobilis and / or Achillea collina plants and, if desired, aromas and fragrances extracted from chamomile drug.

It has now been found that the new inclusion complexes according to the invention can be prepared by reacting a) cc, β or y-cyclodextrin complexes or any mixture thereof with an extract of chamomile drug in the form of a solution, or b) a crude one Fermentation broth, which is obtained in the production of cyclodextrin, is reacted with an extract of chamomile drug, or c) a partially prehydrolyzed starch solution is reacted with a chamomile drug extract and the inclusion complex formed is isolated from the reaction mixture.

When carrying out the method according to the invention, an extract made from Flores chamomillae, Achillea collina and Anthemis nobilis plants is used. The extract - the so-called blue oil - and / or aromas and fragrances are known to be made from plant drugs. The complex formation is carried out at 15-80 ° C., preferably at 50 ° C., after which the reaction mixture is cooled with vigorous stirring.

The cyclodextrin-camomile inclusion complexes according to the invention are stable, powdery products which dissociate in the water and thus have camomile activity.

The inclusion complexes can be incorporated into pharmaceutical preparations or cosmetic agents without risk of decomposition of the active ingredient. The usual carriers, binders, lubricants, taste-improving substances and optionally also other pharmaceutically active agents can be used in the preparation of the preparations.

Combined preparations can also be produced which contain the complex of the cyclodextrin with the camomile blue oil and the complex of the cyclodextrin with the aromas and / or fragrances in any ratio.

The use of the blue oil inclusion complex as a pharmaceutical preparation and pharmaceutical intermediate z. B. in powders and ointments is particularly advantageous, since so far only the pharmacologically only ineffective fragrances and flavors in aqueous extracts served for this purpose.

The use of the inclusion complexes according to the invention shows the following advantages:

1. The complexes are made from natural active ingredients.

2. All pharmacologically important components of the active ingredient are retained.

3. The product shows stability against heat, light, oxygen and metal ions.

647 534

4. The product is a crystalline tablet powder.

5. Easily metered, pharmaceutical preparations with a constant active ingredient content can be produced.

The details of the invention are illustrated by the following examples without restricting the scope of the invention to the examples.

example 1

10.0 g of β-cyclodextrin (moisture content: 14.46%) are dissolved in 180 ml of 30% by volume ethanolic water at 50 ° C. with constant stirring. A solution of 1 g of chamomile oil in ethanol diluted ten times is added dropwise to the β-cyclodextrin solution. 3-4 minutes after the addition, the system becomes cloudy and the crystalline adduct begins to excrete. The system is then slowly cooled to room temperature after 4.5-5 hours. The stirring stops and the complex is kept in the refrigerator for 16 hours. The mixture is filtered through glass filters and dried over phosphorus pentoxide at room temperature. 10.06 g of a crystalline chamomile-oil-β-cyclodextrin complex are obtained.

Active ingredient content of the complexes is: 8.12% and the yield based on chamomile oil is 70.04%. The effectiveness of the complex formation can be increased by using a stirrer with a higher speed.

Empirical formula and molecular weight can only be given in relation to β-cyclodextrin (C6Hi0O5) 7, MBCD: 1135.0. The average molecular weight of the sesquiterpene derivatives of chamomile oil is approx. 230, the average molecular weight of the complex is approximately 1460 with approximately 7% water content.

A structural formula of the product can only be given for the cyclodextrin, the other active ingredient components of the chamomile active ingredient are not all yet known.

The product produced according to Example 1 is a light blue, microcrystalline powder which has a slight smell of chamomile. The product has no melting point, it begins to decompose at around 200 ° C, this temperature is characteristic of the decomposition of the β-cyclodextrin.

Solubility:

in distilled water: 0.030 - 0.035 g / 100 ml in 96% ethanol: 0.030 g / 100 ml in benzene and in chloroform only the oil dissolves, ß-cyclodextrin is practically insoluble in these solvents. (The listed data refer to 25 ° C.)

The aqueous solutions of the complexes are always a bit opal.

The complex is stable at room temperature and can be stored for at least five years without decomposition.

The stability of the product according to Example 1 against oxidation is shown in Table I.

Table I

Oxygen consumption ul / mg

time

(Hours)

Chamomile oil

ß-CD chamomile complex

70

6

2nd

80

14

4th

120

18th

5

160

23

7

200

30th

7

240

58

7

280

80

7

320

100

7

3rd

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

647 534

The oxygen consumption of the complex can be neglected compared to the oxygen consumption of pure chamomile oil.

When administered per os, either chamomile oil or cyclodextrin are toxic. The two components do not form a covalent bond and the complex dissociates under physiological circumstances.

Evidence of activity by examining the effects of the reticulo-endothelial system

The phagocyte function of the reticulo-endothelial system is caused by histamine as a chemical activator. Histamine shows that the endothelial cells of the peripheral capillary veins quickly become phagocytes, which in their body, like the RES cells of the liver, spleen or bone marrow, accumulate the injected ink.

Since chamomile also releases histamine and activates RES, the effectiveness of pure chamomile oil and inclusion complex can be compared by following the elimination of the ink injected into the bloodstream.

CFLP male mice with a body weight of 25 (± 2) g were used as experimental animals (CFLP means an international strain possessing the indicated genetic information). The methodology corresponds practically to the methodology of Jancsó (Jancsó, M .: OrvosokLapja, 1947, III, 28.1025). 0.5 ml of 10% Indian ink (25 g body weight) in a physiological saline solution was injected into the tail vein. 1% gelatin was added to this solution to stabilize the colloidal system. A suspension was used which contains carbon particles with a diameter of only 0.2-1 | x, since a solution with larger particles clogs the pulmonary arteries and the animals die of embolism. Before the ink was injected, 0.5 ml of physiological saline was injected under the skin of the mice twice. The animals were treated with 5 mg of chamomile oil and with 5 ml of chamomile oil-containing product from Example 1 one hour before the injection of the ink orally. The elimination of the ink was monitored photometrically.

After the intravenous administration of the ink, 10 ml of blood was sucked into the measuring pipette every 5 minutes, the blood was homogenized in weakly alkalized water, after which the light absorption of the solution was determined photometrically.

The elimination of the ink from the blood in the control animals and in the treated animals was summarized in Table II.

The toxicity studies of the chamomile-β-cyclodextrin inclusion complex show that the complex is not toxic.

10 female mice (body weight 20-25 g) received in the form of a suspension chamomile complex per os up to 3000 mg / body weight kg (= corresponds to 234 g active substance / body weight kg), or 10 male mice (body weight 20 - 25 g) received similar circumstances the complex up to 3000 mg / body weight kg (= corresponds to 264 mg / body weight kg) and no toxicity was observed. 10 female and 10 male rats (body weight: 150-200 g) received 5000 mg / body weight kg of chamomile complex (= 430 mg of active ingredient body weight kg). No toxicity was observed in this case either.

Table II

Elimination of the ink from the blood. (The administration of the Indian ink increased the absorbance of the blood by an average of 25%, the information in the table shows the reduction in the same in groups of 8 animals (average)

Time after administration

Eti - E, 2nd

range of ink

• 100

E "

control

Chamomile oil

Product after

example 1

between

10-20 minutes "

2.63

7.78

6.75

between

20-30 minutes

3.43

3.30

5.60

between

30-40 minutes

1.69

5.47

4.67

between

10 - 40 minutes

8.15

16.55

17.12

a total of

x = The exact value of the absorbance regarding time 0 cannot be determined

Et = the extinction measured after the injection of the ink

E0 = The absorbance measured before the ink was injected.

Example 2

Production of the chamomile aroma-β-cyclodextrin inclusion complex:

10 g of β-cyclodextrin were dissolved at 50 ° C. in 30% by volume ethanolic water, after which 2.5 g of camomile aroma, which was obtained from 30 g of chamomile flower, was added in solution in 10 ml of ethanol. In the 10th-12th Minute after the addition, the system becomes cloudy, after which the heating is switched off and the reaction mixture is cooled to room temperature with constant stirring for 4 hours. The mixture is kept in the refrigerator for 16 hours, filtered through a glass filter and dried over phosphorus pentoxide. 10.8 g of yellow-white crystalline product are obtained, which contains about 12% of active ingredient (% by weight).

The extract of Roman chamomile (Anthemis nobilis) is preferably used to produce the complex containing the aroma and fragrances of the chamomile flower, since this drug contains only a small amount of the components characteristic of blue oil and is mainly the source of aromas and fragrances.

Example 3

Sensory qualification of the "complete" chamomile tea.

The product according to Example 1 contains all the pharmacologically important components of the chamomile, but not the components which give the characteristic fragrance of the chamomile. In most cases it is not necessary either, but in some cases the fragrance may also be desirable. The product according to example 2 contains these fragrances, so the "complete" chamomile tea can be produced by combining the two products.

The following samples are compared accordingly: 4.5 g of the product according to Example 2 (chamomile aroma complex) + 0.5 g of the product according to Example 1 (chamomile oil complex) in one liter of water and 2.2 g of chamomile flower boiled in one Litre water.

The test was carried out using a comparative sample. Couples of chamomile tea and tea made from cyclodextrin inclusion complexes were found among the samples. The samples were heated to 20 ° C and 40 ° C, respectively, and because of the elimination of the subjective effect of the different color of the samples, the samples were placed in paper-covered vessels.

The sensory examination was carried out by 11 observers at 20 and 40 ° C.

The identity was correctly determined by 10 people, from which the tea of the chamomile flower has 3 people as better

4th

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

5

647 534

and the cyclodextrin inclusion complex mixture was found to be better by 7 people.

Accordingly, the significance of the difference sample is 99.9%

the significance of the quality sample 99.0%

The correct answer given by observers rated the tea obtained from the cyclodextrin inclusion complex by solution with a significance of 99.9% for better.

Example 4

1 g of the product according to Example 1 corresponds to 8.40 g of air-dry drug. The product can be used in the veterinary field in various cases of intestinal inflammation in pigs, cattle, horses, dogs and cats as follows.

a) In any case where inflammation of the stomach or intestines causes dietary errors. After starving to death, the animal is given 50-150 mg of complex / body weight kg or a tablet of the appropriate dose 3-5 times a day for 2-3 days until the march stops. The product can preferably be combined with the usual amount of activated carbon in therapy. Until complete recovery, the animal is given an aqueous solution of body temperature instead of drinking water, which is produced from the chamomile complex according to Example 1.

b) In cases in which the various serious stomach and intestinal inflammations are caused by pathogens (coli, etc.), the chamomile complex can be treated with another antibacterial pharmaconence after treatment with a laxative. Oxolinic acid can be combined. This combination can be administered either in drinking water or mixed in the feed until the animal has recovered. Instead of drinking water, an aqueous solution made from camomile-cyclodextrin complex is also given to the animals until they have recovered.

c) In the case of external inflammation of the various domestic animals, a powder or granule containing chamomile-cyclodextrin is placed between gauze bands on the inflamed skin, and the gauze band is immersed in water for a short time before application.

d) A solution or suspension prepared from the product according to Example 1 is used in the case of conjunctivitis or inflammation of the oral cavity, inflammation of the anus or for irrigation of the uterus.

e) In a few days after the sale, the piglets have a non-specific, ie non-infectious enteritis with a probability of 30-90%. The frequency and intensity of the enteritis can be reduced, or the number of days required to cure the enteritis can also be reduced if a camomile oil-β-cyclodextrin prepared according to Example 1 is used in the feed. At the same time, increased feed intake or better feed utilization can be observed.

3.42 kg of chamomile oil-ß-cyclodex-trin complex prepared according to Example 1 were made up to 50 kg with flour and mixed until homogeneous. The permix was diluted to 200 times its volume with feed, i.e. 10,000 kg of weaned piglet feed were produced, the 0.5 kg (an average daily feed intake of a weaned piglet of heel age) containing 15 mg of chamomile oil. The experiments were carried out in 2 different pig farms. In Farm I, tetrahybrid pigs were chipped at the age of 28 days and the animals were fed dry feed using the self-feeding method of the Hungarian factory Phylaxia. In Farm II, similar pigs of the same age were fed with dry feed from the trough according to the Central Soya recipe. The number of animals and the test results are shown in the following tables.

The tables show that the average weight gain per day in the chamomile complex-treated group was significantly better than that in the control group, the amount of feed required for 1 kg weight gain is 5 smaller at the same time.

The animals showed a daily weight gain of 25-30 g, and for 1 kg weight gain, 100-125 g less feed was necessary at the same time.

10th

Farm I

Use, weight gain and feed conversion parameters

with chamomile

Control group

treated

groups

Age (days)

at the beginning of the experiment

29.56 ± 4.60

25.50 ± 2.14

at the end of the experiment

49.56 ± 4.60

45.50 ± 2.14

Number of animals (pieces)

at the beginning of the experiment

309

306

at the end of the experiment

299

293

Use (piece)

10 (3.24%)

13 (4.25%)

Enteritis

8 (2.59%)

12 (3.92%)

Other

2 (0.65%)

1 (0.33%)

Average weight (kg)

at the beginning of the experiment

6.29 ± 1.12

5.58 ± 0.71

at the end of the experiment

12.88 ± 2.12

11.47 ± 1.17

Average

Weight gain (kg)

6.59

5.89

Average

Weight gain per day (g) 330

295

Total food consumed

(kg)

4350

4050

Average feed

consumption per day (g)

715

676

to 1 kg weight gain

required amount of feed (kg)

2,171

2,296

Farm II

Use, weight gain and feed conversion

parameter

with chamomile

Control group

treated

groups

Age (days)

at the beginning of the experiment

33.17 ± 3.54

29.68 ± 2.84

at the end of the experiment

60.17 ± 3.54

56.68 ± 2.84

Number of animals (pieces)

at the beginning of the experiment

234

211

at the end of the experiment

225

206

Use (piece)

9 (3.85%)

5 (2.37%)

Enteritis

6 (2.56%)

3 (1.42%)

Other

3 (1.28%)

2 (0.95%)

Average weight (kg)

at the beginning of the experiment

8.93 ± 1.35

7.95 ± 1.14

at the end of the experiment

17.20 ± 2.23

15.54 ± 2.10

Average

Weight gain (kg)

8.27

7.59

Average

Weight gain per day (g) 306

281

Total food consumed

(kg)

4850

4206

Average feed

consumption per day (g)

783

747

to 1 kg weight gain

required amount of feed (kg)

2,556

2,658

647 534

6

Children's powder composition:

Example 5

Chamomile extract ß-CD Azulenol 100% ß-CD basic magnesium carbonate talc

5.0 g 5.0 g 70.0 g 920.0 g

1000.0 g tongue:

Chamomile extract-ß-CD

5.0 g

Azulenol 100% ß-CD

5.0 g

kaolin

130.0 g

Magnesium carbonate

130.0 g

Starch (ANM)

116.0 g

Cetyl alcohol

20.0 g

Magnesium stearate

30.0 g

Zinc oxide

50.0 g

Talcum

514.0 g

1000.0 g

Mesh size of 0.16 mm can be screened without residue. The active ingredient prepared in this way is mixed with the starch (ANM-Amylum non mucilaginosum special powder starch) and the other powder substances are also mixed in larger quantities. After sieving again, the mixture is poured into scattering boxes and possibly pressed into a cylinder shape.

Camomiles and azulenol-ß-CD inclusion complexes are atomized thoroughly so that the mixture can be sieved through a sieve of 0.16 mm mesh size without residue (Ph. Ed. VI. Sieve classification). The mixture is then mixed with the basic magnesium carbonate and talc. The finished powder is sieved again and filled into suitable sprinkling boxes.

Example 6

Dry shaving powder

10th

The chamomile and azulenol-ß-CD inclusion complexes are thoroughly atomized so that the mixture is passed through a sieve

Tea tablet composition:

15

Example 7

Chamomile extract-ß-CD 20.0 g

Azulenone 100% β-CD 20.0 g

Ascorbic acid 44.0 g

Sodium carbonate 15.0 g

Glycerol monostearate 1.0 g

20th

25th

Granules are produced from ascorbic acid and sodium bicarbonate with glycerol monostearate according to the general rules of drug technology. The camomiles and azulenol-ß-CD inclusion complexes are atomized thoroughly so that the mixture can be sieved through a sieve with a mesh size of 0.16 mm without residue (Ph. Hg. VI sieve classification). The camomiles and azulenol-ß-CD inclusion complexes are mixed with the ascorbic acid and sodium bicarbonate granules, after which 0.5 g of tablets are pressed.

Example 8

tea

30th

Component ratio when making tea: 1.8 g of chamomile drug extract-ß-CD complex and 0.2 g of chamomile oil-ß-CD complex are dissolved in 100 ml of hot water.

M

Claims (13)

647 534 PATENT CLAIMS 1. Cyclodextrin-chamomile inclusion complex, characterized in that the complex contains cyclodextrin molecules as guest molecules and an extract from camomile drug as a closed molecule. 2. Cyclodextrin inclusion complex according to claim 1, characterized in that the complex contains as an included compound an extract from Flores chamomillae and / or Anthemis nobilis and / or Achillea collina plants. 3. Cyclodextrin inclusion complex according to claims 1 and 2, characterized in that the complex contains «blue oil» molecules extracted from camomile drug as enclosed molecules. 4. Cyclodextrin inclusion complex according to claims 1 and 2, characterized in that the complex contains camomile drug extracted fragrances and / or aromas. 5. A process for the preparation of cyclodextrin-chamomile inclusion complexes, characterized in that a) one of the a, β- or y-cyclodextrin complexes or any mixture thereof is reacted in the form of a solution with an extract from chamomile drug, or b ) a crude fermentation broth obtained in the production of cyclodextrin is reacted with an extract of chamomile drug or c) a partially prehydrolyzed starch solution is reacted with a chamomile drug extract and the inclusion complex formed is isolated from the reaction mixture. 6. The method according to claim 5, characterized in that one uses an extract from Flores chamomillae and / or Anthemis nobilis and / or Achillea collina plants. 7. The method according to claims 5 and 6, characterized in that one uses blue oil made from chamomile drug. 8. The method according to claims 5 and 6, characterized in that one uses fragrance and / or aroma substances extracted from chamomile drug. 9. The method according to claim 5, characterized in that one carries out the complex formation at 15 - 80 ° C, preferably 50 ° C and the reaction mixture is slowly cooled with vigorous stirring. 10. Cyclodextrin inclusion complex preparation characterized by the content of any mixture of the Cyclodex-trin-chamomile inclusion complexes according to claims 1 to 4. 11. Cyclodextrin inclusion complex preparation according to claim 10, characterized by an additional content of carriers, diluents, binders, lubricants and / or taste-improving substances. 12. Cyclodextrin inclusion complex preparation according to claim 10, characterized by an additional content of pharmaceutically suitable carriers, taste-improving substances, binders, lubricants and / or other pharmaceutically active compounds. 13. Cyclodextrin inclusion complex preparation according to claim 10, characterized by an additional content of cosmetic ingredients.