DD146893A1 - PROCESS FOR PREPARING CYCLODEXTRIN-COMBUS INCLUSION COMPLEXES - Google Patents

Abstract

With the help of the invention, the active ingredient, the aromas and fragrances of chamomile can be stabilized. The inclusion complexes simplify the treatment, and the dosage can be more accurate than before. According to the invention, a) an alpha, beta or gamma cyclodextrin complex or a mixture of these complexes is reacted in the form of a solution with an extract prepared from chamomile drug or b) a crude fermentation broth obtained in the preparation of cyclodextrin is reacted with a chamomile extract or c) reacting a partially prehydrolyzed starch solution with a chamomile extract, after which the inclusion complex formed is isolated from the reaction mixture.

Description

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»Process for the preparation of cyclodextrin-camomile inclusion complexes

Field of application of the invention:

The invention relates to a process for the preparation of cyclodextrin-camomile inclusion complexes or preparations containing these complexes.

Characteristic of the known technical solutions:

Chamomile (Flores-chamomillae), the widely used yarrow (Achillea collina) and Roman chamomile (Anthemis nobilis) have been known for a long time for their active ingredients and are used in therapy for a long time.

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The flowering of the plants is used, the decoction of which is effective in the case of intestinal inflammation, gastritis and cystitis inside and in the case of conjunctivitis, inflammation of the maxillary sinus and ear canal inflammation as an external envelope. The kamaculum contained in the essential oil of chamomile releases histamine, activates the reticulo-endothelial system and promotes the healing process of the torpid-like persistent inflammatory processes.

The application of the chamomile drug can be done in two ways:

1) preparing from the chamomile an aqueous decoction (chamomile tea) containing the flavonoids, coumarins and chamomile characteristic fragrances and flavorings, but contains only a small Teil.der pharmacologically active essential oil-terpene components,

2) make chamomile oil. The oil is not used directly, so it is given to ointments, creams, powder in general to anti-inflammatory drugs. The oil-containing preparations lose their stability quickly. The oil also does not have the characteristic camomile aroma.

The important active ingredients of chamomile oil are:

1- Bizabolol Camazulas Bizabolol-oxide I Bizabolol-oxide II Pharnezenes Herniarin

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A further disadvantage of using the flowers is that the content of active ingredient is reduced during storage and the use of the drugs is accompanied by microbiological and parasitic infections. Although the blue oil extracted from the flower is free from microbiological contamination, its stability is even lower. The active ingredient content in the blue oil containing preparations can only be guaranteed for a short time. The stabilization of the drug is not solved in any commercial preparation.

The commercial chamomile preparations (in liquid or tableted form) have a very different composition than the natural chamomile, which contain only a small portion of the original active ingredients and predominantly decomposition products. Only a short time after production, the products are reminiscent of chamomile, and a chemical analysis has already revealed significant differences.

A commercially available liquid product was analyzed by chromatography and six months after the preparation only two undecomposed camomile oil components could be detected in the preparation. One component was Kamazulen, but only 15-20 % of Kamazulengehaltes chamomile oil. But it is also probable that the substance held for kamazulene is only azulene (artificially produced azulene). In the camomile drops were still traces of 1-bizabolol and two other likely decomposition products can be detected. The product smells slightly fiery and is a brown alcoholic liquid.

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

Instant chamomile tea was also analyzed. "According to chromatographic analysis, the tea did not contain any of the volatile oil components enumerated above. With the specific terpene reagent an unidentifiable decomposition product could be detected. The product contains a large number of plavones, which are believed to be different glycosides of the apigenin plavone.

Aim of the invention; ,

With the aid of the process according to the invention, the active ingredient, the aromas and fragrances of chamomile can be stabilized. In accordance with the invention, inclusion complexes are prepared which contain liquid actives and flavors included in a solid carrier (cyclodextrin). The inclusion complexes allow for easier treatment and the dosage can be made much more precise.

Presentation of the invention of the invention:

The cyclodextrins are glycopiranose closed rings whose steric configuration can be characterized by a hydrophilic surface and a hydrophobic closed inner space. When these cyclodextrins are reacted in an aqueous solution with hydrophobic molecules: so-called inclusion complexes are formed. The molecules of the drug or flavor included in the inclusion complexes are protected to a great extent from external agents (such as oxygen, heat, light, etc.). The active compounds can be stabilized by complex formation and can be formulated directly by means of pharmaceutical-technological methods.

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The present invention relates to cyclodextrin-camomile inclusion complexes consisting of cyclodextrin as a guest molecule and of a camomile extract as trapped molecules.

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

It has now been found that the novel inclusion complexes can be prepared according to the invention by

a) (A. ȧ- or T-cyclodextrin or any mixture thereof with an extract prepared from chamomile drug prepared in the form of a solution, or

b) reacting a crude Permentbrühe, which is obtained in the production of cyclodextrin, with an extract prepared from chamomile drug known, or

c) reacting a partially prehydrolyzed starch solution with an extract prepared as is known from chamomile drug and isolating the inclusion complex formed from the reaction mixture.

In carrying out the method according to the invention, an extract prepared from Flores chamomilleae, 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 ⁰ C, preferably at 50 ⁰ C, Y / onach the reaction mixture is cooled with vigorous stirring.

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

The inclusion complexes can _e G without moving the decomposition of the active ingredient in pharmaceutical preparations or cosmetic agents may be incorporated. In the preparation of the preparations, the usual excipients, · binders, lubricants, taste-improving substances, and optionally also other pharmaceutically active agents may be used.

Also comiblated preparations can be prepared which contain the complex of the cyclodextrin with the camomile blue oil and the complex of the cyclodextrin with the flavors and / or fragrances in any ratio.

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

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

1. The complexes are prepared from natural active substances.

2. All pharmacologically important components of the active substance are contained in the complex.

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

4. The product is a crystalline tablettable powder.

5. It is possible to prepare easily dosed pharmaceutical preparations; v with a constant active substance content.

From example:

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

example 1

10.0 g of .beta.-cyclodextrin (moisture content: 14.46% are dissolved in 180 ml of 30 Vol% ethanol at 5O ⁰ C with continuous stirring, a solution is added dropwise 1 g camomile oil in ten fold diluted ethanol, to beta-cyclodextrin solution.. 3-4 minutes after addition, the system becomes cloudy and the crystalline adduct begins to precipitate, then the system is cooled slowly to room temperature after 4.5-5 hours, stirring stops and the complex becomes 16 hours long The mixture is filtered through glass filters and dried over phosphorus pentoxide at room temperature to give 10.06 g of a crystalline chamomile oil-β-cyclodextrin complex.

The active substance content of the complexes is: 8.12 % and the yield based on chamomile oil is 75.04 %. » 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 (CgEL ₀ O, -), ^, *% cD ^: ^ 35 The average molecular weight of the sesquiterpene derivatives of camomile oil is about 230, the average molecular weight of the complex being about Ί% water content about 1460.

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

The product prepared according to Example 1 is a light blue, microcrystalline powder that smells a little like camomile. The product has no melting point, it begins to decompose at about 200 ⁰ C, this temperature is characteristic of the decomposition of the ß-cyclodextrin.

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Solubility: in distilled water: 0,030-0,035 g / 100 ml in 96% ethanol: 0,030 g / 100 ml in benzene and in chloroform dissolves only the oil, ß-cyclodextrin is practically insoluble in these solvents «(see above) to 25 C.)

Aqueous solutions of complexes are always a little 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

Time oxygen consumption / Ul / mg

(Hours) ^L

Chamomile oil. ß-CD chamomile complex

70 6 2

80 14 .4

120 18 5

160 23 7

200 30 7

240 58 7

280 80 7

320 100. 7

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

Neither chamomile oil nor cyclodextrin administered per os are toxic. "The two components do not form a covalent bond and the complex dissociates under physiological conditions.

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Demonstration of activity by studying the effect of the reticulo-endothelial system

The phagocyte puncturing of the reticulo-endothelial system is caused by histamine as a chemical activator. Histamine causes the endothelial cells of the peripheral capillary veins to rapidly transform into phagocytes that accumulate in their bodies, similar to the RES cells of the liver, spleen or bone marrow, the injected ink.

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

As experimental animals CPLP male mice of a body weight of 25 (± 2) g were used (CPLP means an international, indicated genetic information possessing strain). The methodology corresponds practically to the method of Janeso, M .: Orvosok Lapja, 1947, III, 28, 1025). Into the tail vein was injected 0.5 ml of 10% Indian ink (25 g body weight) in a physiological saline solution. To this solution was added 1 % gelatin to stabilize the colloidal system. A suspension containing carbon particles only 0.2-1 / a in diameter was used because a larger particle solution clogs the pulmonary veins and the animals die from embolism. Before injection of the ink, 0.5 ml of physiological saline was injected twice under the skin of the mice. The animals were treated with 5 mg camomile oil and with 5 ml camomile oil-containing product of Example 1 one hour before the injection of the ink per os. The elimination of the ink was monitored photometrically.

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By intravenous administration of the ink, 10 ml of blood was aspirated 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 camomile β-cyclodextrin inclusion complex show that the complex is non-toxic. ·

10 female mice (body weight 20-25 g) were given in the form of a suspension of chamomile complex per os up to 3000 mg / kg body weight (= corresponds to 234 mg V / irkstoo / kg body weight), or 10 male mice (body weight 20-25 g) Under similar circumstances, the complex was given up to 3000 mg / kg body weight (= 264 mg / kg body weight) with no toxicity observed. 10 female and 10 male rats (body weight: 150: 200 g) were given 5000 mg / kg body weight chamomile complex (= 430 mg of active ingredient / κβ body ^weight!), Also in this Pail no toxicity could be observed.

Table II

Elimination of the ink from the blood (the administration of the ink increased the extinction of the blood on average by 25 %, the data in the table shows the reduction of the same in groups of 8 animals (average

Duration E, - E,

after the ___1 2 · 1OO

Administer _F

the ink _ ^ ο

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control KamillendI Product according to 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 in total 8.15 16.55 17.12

χ. = The exact value of the extinction regarding time can not be determined

E, = The extinction measured after injection of the ink at time t

E = the absorbance measured from the injection of the ink.

Example 2

Production of Chamomile-β-Cyclodextrin Inclusion Complex

10 g beta-cyclodextrin were dissolved at 50 ⁰ G in 30 Vol.tigern ethanol whereupon 2.5 g camomile flavor, which was obtained from 30 g Chamomile, was added dissolved in 10 ml of ethanol. 10-12. Minute after the Z _u reproducing the system becomes cloudy, after which the heating is turned off and the reaction mixture is cooled for 4 hours with constant stirring to room temperature v / ith. The mixture is kept for 16 hours in the refrigerator, filtered through glass filters and dried over Phospliorpentoxid. This gives 10.8 g of yellow-white crystalline product which contains about 12 % of active ingredient. (% By weight).

For the preparation of the aroma and fragrances containing the chamomile complex is preferably used the extract of the Roman chamomile (Anthemie nobilis) as this drug contains the characteristic of the blue oil components only to a small extent, and is predominantly the source of aroma and fragrances.

Example 3

Sensory qualification of the complex "chamomile, it"

The product according to Example 1 contains all the pharmacologically important components of chamomile, but not the components which cause the characteristic aroma of chamomile. In most cases, it is not necessary, but in some cases, the fragrance may be desirable. The product of Example 2 contains these fragrances, so the complex "chamomile tea" can be prepared by the combination of the two products.

Accordingly, the following samples are compared: 4.5 g of the product of Example 2 (camomile complex) + 0.5 g of the product of Example 1 (chamomile oil complex) boiled in one liter of water and 2.2 g of camomile blossom in one Litre water.

The investigation was carried out with a comparative sample. Among the samples were chamomile tea and tea from cyclodestrin inclusion complexes. The samples were heated to 20 ⁰ C or 40 ⁰ G, and because of the elimination of the subjective effect of the different color of the samples in this covered with paper vessels were presented.

The sensory examination was performed by 11 observers at 20 and 40 ⁰ G.

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The identity was correctly determined by 10 persons, from which the tea of the chamomile flower 3 persons judged better and the cyclodextrin inclusion complex mixture was found to be better by 7 persons.

Accordingly is

the significance of the difference sample 99.9 %

the significance of the quality sample 99 »0%.

The correct answer given observers evaluated the tea obtained from cyclodextrin glucosamine 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 may be used in the veterinary field in various cases of intestinal inflammation in pig, cattle, horse, dog and cat.

a) In every pail in which the inflammation of the stomach or intestine causes dietary errors. After starving previously, the animal is given 50-150 mg complex / kg body weight or equivalent tablet 3-5 times a day for 2-3 days until diarrhea ceases. The product may preferably be combined with an amount of activated charcoal commonly used in therapy. Until complete recovery, the animal is given an aqueous solution of body temperature instead of drinking water, which is prepared from the chamomile complex of Example 1.

b) In such cases in which the various serious gastric and intestinal inflammations caused by pathogens (coli, etc.), the chamomile complex can after

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a treatment with a laxative with other antibacterial drugs e.g. Oxolic acid are combined. ' This combination can be administered either in drinking water or mixed in the putter until recovery of the animal. In these cases, instead of drinking water, an aqueous solution prepared from chamomile-cyclodextrin complex is given to the animals until their recovery.

c) In the case of external inflammation of the various domestic animals, a powder or granulate containing chamomile-cyclodextrin is placed between gauze bandages on the inflamed skin, the gauze bandage 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 oral inflammation, orifice inflammation or for the irrigation of the uterus.

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

3.42 kg camomile oil-β-cyclodextrin complex prepared according to Example 1 were supplemented with flour to 50 kg and homogenized. This mixture was diluted to 200 times its volume with feed, ie 10 000 kg of seedling forage were produced, which contained 15 mg of chamomile oil in 0.5 kg (average daily feed intake of one heifer).

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held. The experiments were carried out in 2 different pig farms. In Farm I, tetrahybrid pigs were cut off at the age of 28 days and the animals were fed on the formula of the Hungarian factory Phylaxis with the self-feeding method with dry food. In Farm II, similar pigs of the same age were fed dry fodder from a Central Soya recipe trough. The number of animals and the test results are shown in the following tables.

It is apparent from the tables that the average weight gain per day in the chamomile complex-treated group was significantly higher than that in the control group, the amount of food required for 1 kg weight gain being simultaneously smaller.

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

Farm I use, weight gain and feed conversion parameters

Chamomile treated group Age (days) control groups 50 + 2,14 at the beginning of the 29.56 + 4.60 trial 50 + 2,14 at the end of the 49.56 + 4.60 trial 25 Number of animals (pieces) 45, 306 at the beginning of the 309 trial 293 at the end of the 299 trial (4.25 %% Consignment (piece 10 (3.24 %) (3.92 %) Enteritis 8 (2.59 %) 13 (0.33%) Other 2 (0.65 %) 12 Average weight (kg) 1 58 + 0.71 at the beginning of the 6.29 + 1.12 attempt 47 + 1.17 at the end of the 12,88 + 2,12 attempt 5, 5.89 Average weight gain (kg) 6 ^ 59 11 295 Average. Weight gain per day (g) 330 4050 Total consumed feed (kg) 4350 676 Average consumption per day (g) 715 2,296 amount of food required to 1 kg weight gain (kg) 2,171

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Farm II use, weight gain and feed conversion parameters

Chamomile treated group 8.93 + 1.35 4850 2,556 control group Age (days) 17.20 + 2.23 Average feed consumption per day (g) 783 "at the beginning of the trial 33.17 + 3.54. Average weight gain (kg) 8,27 Quantity of feed required for 1 kg weight gain (kg) 29.68 + 2.84 at the end of the trial 60.17 + 3.54 Average weight gain per day (g) 306 56.68 + 2.84 Number of animals (pieces) Total consumed feed (kg) at the beginning of the trial 234 211 at the end of the trial 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 trial 7.95 + 1.14 at the end of the trial 15.54 + 2.10 7.59 281 4206 747 2,658

_ Ψ / £ - 18 Example 5 Children's powder

Composition: Chamomile extract β-CD 5.0 g

Azulenol 100% β-CD 5.0 g

Basic Hagnesium Carbonate 70.0 g Talcum 920.0 g

1000.0 g

Camomiles and azulenol-β-CD inclusion complexes are milled so that the mixture can be screened through a sieve of 0.16 mm mesh size without residue (Ph. Hg. VI. Siebenklassifikation). The mixture is then mixed with the basic magnesium salt and talcum. The finished powder is sieved once more and filled into suitable litter boxes.

Example 6

Dry shaving powder

Composition: Chamomile extract ~ ß-CD 5.0 g

Azulenol-100 μl, β-CD 5.0 g

Kaolin · 130.0 g

Hagnesium carbonate 130.0 g

Starch (AlM) 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

The chamomile and azulenol-β-CD inclusion complexes are ground so that the mixture can be screened through a sieve of 0.16 mm mesh without residue. The thus prepared active ingredient is mixed with the starch

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(ΑΝΙί-Amylum non mucilaginosum special powder strength) and also the other powders are mixed in larger quantities. The mixture is filled after re-screening in Streubüchsen and possibly pressed in a cylindrical shape.

Example 7 Tea tablet

Composition: Chamomile extract β-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

From ascorbic acid and sodium carbonate, granules are made with glycerol monostearate according to the general rules of pharmaceutical technology. The chamomile and azulene-β-CD inclusion complexes are ground so that the mixture can be sieved through a sieve with a mesh size of 0.16 mm without residue (Ph. Hg. VI screening classification). The camomiles and azulenol-β-CD inclusion complexes are mixed with the ascorbic acid and sodium bicarbonate granules, after which 0.5 g of tablets are pressed.

Example 8

Component ratio in tea production:

1.8 g chamomile extract-β-CD complex and 0.2 g camomile oil-β-CD complex are dissolved in 100 ml of hot water,

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Claims (5)

Invention claim: 1. A process for the preparation of cyclodextrin camomile inclusion complexes and preparations containing these complexes characterized in that a) reacting one of the # - j ß- or T-cyclodextrin complex or any mixture thereof in the form of a solution with an extract prepared from chamomile drug or known b) reacting a crude permuent broth obtained in the preparation of cyclodextrin with an extract prepared as is known from chamomile drug or c) reacting a partially prehydrolyzed starch solution with an extract which is known to be produced from chamomile drug, the inclusion complex formed isolated from the reaction mixture and optionally processed into preparations. 2. The method according to item 1, characterized in that one uses an extract made from Flores chamomillae and / or Anthemis nobilis and / or Achillea collina plants. 3. The method according to the items 1 and 2, characterized in that one uses blue oil produced from chamomile drug. 4. The method according to points 1 and 2, characterized in that one uses extracted from chamomile drug fragrances and / or flavorings. 5. The method according to item 1, characterized in that one carries out the complex formation at 15-80 ⁰ C, preferably 50 C and slowly cooling the reaction mixture with vigorous stirring. Process according to items 1 to 5, for the preparation of cyclodextrin inclusion complex preparations, characterized in that cyclodextrin-camomile inclusion complexes, which were prepared according to items 1 to 4, in any ratio - if desired, with carriers, diluents, binders, lubricants , and flavor-enhancing substances - mixed.