CS223972B2 - Method of makinh the medicinal means with contents of inclusive complex of cyclodextrine and cammomile extract - Google Patents

Abstract

An abstract of camomile plant material is stabilised as an inclusion complex with cyclodextrin. The complex can be formulated into pharmaceutical and cosmetic compositions or into animal feeds. The material complexed may be obtained from Flores chamomillae and/or Anthemis nobilis and/or Achillea collina. More specifically the complexed material may be "blue-oil" or aroma and/or flavour extracted from camomile plant material.

Description

The invention also relates to the production of cyclodextrin inclusion complexes and chamomile extract.

Chamomile (FLor ^ es chamomillae) and for medical purposes The widely used cormorant (Achilea collina) and the Roman camomile (Anthemis nodlis) have long been known for their active substances and are used in medicine.

The decoction of the flowers of said plants is used internally and externally for inflammation of the small intestinal mucosa, stomach and urinary bladder inflammation, for example, for inflammation of the spinal cord and external ^{sound in a} cladding. ^K ^ fi ^ Z ^ Z ^] ^L ene comprehensive in chamomile essential oil released in-Ost, activates retinoic oenť ^ ^ ^ KUL dOelL.ál.ní system and promotes healing of refractory chronic inflammatory processes. .

Camomile can be used in two ways.

1. An aqueous camomile odvnr, camomile tea, which contains flavonoids, and has kummriny chul and smell ihalalCeeistickou for 'camomile, but contains only a small proportion ^ fl ^ Oelke Oogiiky active éteric olljoferlnnový = ^CH, or folders.

2. Prepare camomile oil. This oil is not used directly, but is processed to ^{oalSe, to} re ^we powders and pototoě and these ^{p at} pH RAV ^alkyl then at užXvaj-rétOvým disease. The oil is little stable, so. preparations containing it, soon lose their effect. The oil also has no direct chamomile fragrance.

Chamomile contains the following important active ingredients:

1-bizabolol kzmazulen dicycloether bizabool-oxide I bizabool-oxide II Pianos Hmiain> DsThe disadvantage of using chamomile flowers is that the content of active substances keeps decreasing during storage and the drug is then subject to microbiological and paaaaital infection. The so-called blue oil, which can be extracted from flowers, is not subject to infection, but its stability is still minor. The content of the active substances in the blue olives and the preparations containing them can only be guaranteed for a short period of time.

Chamomile preparations in liquid or tabulated form have a completely different composition from natural camomile and both contain only a small proportion of the original active ingredients, but contain a wide range of decomposition products. Just a short time after production, these preparations are reminiscent of aromas and flavors of camomile. , however, chemical analysis reveals significant differences in the composition of chamomile and preparations that should contain it very soon.

In the liquid preparation, which was analyzed cUrvmaauvrεZ ^, 6 months after production, it was possible to detect two components which were formed by decomposition of camomile oil. One of these components was kamazzlen, but contained only 15-20% camomulene from camomile oil. In fact, only azulene, which can also be produced synthetically, is a compound considered to be a kaolin. A trace of l-bizabolol could be isolated from the other two decomposition products from the chamomile drops. The product had a dark brown color and a scent of burns.

In this product, only a single compound of the ethane type could be detected, but this compound was not identical to any one of the wild-type camomile.

Next, tea prepared from spray-dried chamomile was analyzed. After urographic analysis, the tea did not contain any of the above volatile components. Only the specific terpene reagent could be detected as degradation products. The product contained large moons of flavones, predominantly various glycosides of appengine bells.

SUMMARY OF THE INVENTION It is an object of the present invention to stage the aromatic and flavoring substances of camomile. By the process according to the invention, inclusion complexes can be obtained which contain the liquid active ingredient together with the solids and flavoring substances which are cyclodextrins. This allows tomjjlexy appointed Surveyor ^ ^ UUI priest ⁱⁿ the ^E and ^{P can} Comms-dosed ^^ Ankum.

CyУkodunXrioy are substances derived from glykvpyrznos, ie a ring closure ^to jejcehž sterlcM he ^f ^ J ^ J ^ ^gu ^ ce and the character! ZOV ^ and ^p tyddofilním ovrchem and tyteofefoním Větřní enclosed space. When these dextrins are brought into contact with the hydrophobic molecules in the nutrient solution, so-called inclusion complexes are formed. Mooekuly drug or aromatic substances enclosed in the thus formed inclusion kommlexu are largely ^CHR n ^{currency p} efore external influences PWD ^l i ^K lz ^up R E ^{D effects due} an oxygen ^to u, ^u n ^{l lz,} light and? fobně. The active ingredient can also be controlled by the formation of comlexes and processed immediately to form pharmaceutical preparations in a conventional manner.

The present invention relates to a process for the production of chamomile and cycloantine sliding complexes which jump from the cyclic outer shell and from the camomile extract as closed inclusions. The chute contains an extract made from Flores chamovillan and / or Anthemis leg and / or Achilles collina also contains aromatic and flavoring substances of camomile. It has now been found that the novel inclusion complexes of the present invention can be obtained by reacting alpha, betane, or ganaaccyioextrin, or any mixture thereof, with a solution obtained from a chamomile drug.

Accordingly, the present invention provides a process for the manufacture of a medicament comprising cyclodexamine and camomile inclusion kits, characterized in that the reaction comprises alpha, betane or gallaachylleetin or any mixture thereof in the form of a solution with an extract obtained from ^h eřmánkové ^d ro ^Gy known zpčisobem at temperatures 15 and ⁸⁰ ° C, above ^h o ^d ou 50 ° C and the reaction mixture was cooled slowly with vigorous stirring. the inclusion complete, the reaction mixture is isolated and then together with a carrier , the pharmaceutically přijaeelným ctatovými ^ ^p ^ weave oji.vy ^to luznými wefts and ^p opřípa ^ga Dani oaths treated with n ^and therapeutic agent.

The cycloethyl and camomile inclusion sets produced by the method of the invention are stable, powdered products which dissociate in water and have an effect similar to that of camomile.

III-uzií sets of this invention can be processed without risk of decomposition of active agents to f ^ AIMA ^ (^ ι ^ j: ical compositions or cosmetic compositions. In the manufacture of ^preparations can be used ^b ěžnýc ^h из! ^ ^ OLV,? uzný ^ substances, ^LA Tek improving Mut, optionally also, other pharmacologically active substances.

It is also possible to produce combination formulations which convert the whole ^to blue oil and blue oil and the complete cyclodil oil and flavor and / or flavorings in any ratio.

The use of a blue oil complex containing illuclides as a pharmaceutical preparation or as an intermediate for the manufacture of other pharmaceutical preparations, for example, powders or is very advantageous, since up to now pharmacologically poorly effective aqueous extracts containing flavorings and drugs have been available.

The use of the complexes produced by the process of the invention has the following advantages:

1. Sets are prepared from natural active ingredients.

2. All pharmacologically important components of the active substance are preserved.

3. The product is very stable to heat, light, oxygen and metal ions.

4. The resulting product is a crystalline tablet powder.

5. Easy-to-dispense pharmaceutical preparations having a stable active ingredient content can be obtained.

·AND

The following detailed examples illustrate the advantages and advantages of the process of the present invention.

Example

10.0 g of beta-hycidextrile (water content 14.4690 was dissolved in 18 ml of 30% ethanol in water at 50 ° C with stirring) and then a solution of 1 g of chamomile oil in 10-fold dilution was added dropwise. ethanol class. 3-4 minutes after the addition was complete · zakaaí a crystalline addition product began to precipitate. the system is slowly cooled over 4 _Г 5-5 hours písSnllSi temperature. the mixture was stirred and stops comp ^ p.et is stored The mixture was filtered through glass and dried at room temperature with phosphorus pentoxide to give 10.06 g of a crystalline complex of chamomile oil and beta-cyclodeetrin.

Heir mnossví complex contains active substances: 8.12% in total, so that the yield of ^{m HE} Sh o ^{eh to} the pouring ^of the efficacy of ^75.04% · ^ orts complex may be increased by using a stirrer having higher rotational speed.

An organic sample and molarity can only be reported with respect to beta-cyclodeetrine, the empirical formula (C 8 H 10) 7, molecular weight 1135.0. The homogeneity of the sesquiterpene derivatives of the camomile oil is approximately 230, the average moisture content at about 7% of the water content is approximately 1460.

The structural formula of the product can only be given with respect to the cycling cycle, the other active ingredients of the camomile are not yet fully understood.

The product produced by the method of Example 1 is a light blue microbyssalic powder with a weak camomile. The product does not have the pulse of thallium ^p s ² ° to 0 ° C in thy ^beta decay, this temperature is the decomposition chaaaacteisticCá beta cyklodeetrinu.

Rozppusnoot: distilled 'water from 0.030 to 0.035 g / 100 m., In 96% ethanol, 0.030 g / 100 ml benzene and in chlorofomiu the rozpouuší only oil' beta cyklodeexrin in these solvents in ^TED matte PRACTICING insoluble, shall bring the ^limb and is is referenced to a temperature of ² 5 ° C.

Aqueous solutions of complexes are always somewhat opalesskuí.

Kexapexes are stable at room temperature and can be stored for at least 5 years without decomposition.

The oxidation stability of the product obtained according to Example 1 is shown in Table 1:

Tabuukal

time (h) Oxygen consumption jul / nig camomile oil complex 70 6 2 80 14 4 1 20 18 5 1 60 23 7 200 30 7 240 58 7 280 80 7 320. . 1 00 7

The oxygen consumption of the complex is determined by comparison with the oxygen consumption of pure camomile oil. .

When administered orally, neither camomile oil nor cycling is toxic. Both components do not form any Ulvalrnt bond and the complex decomposes under physiological conditions.

Determination of efficacy by detecting retilluiloendothelial system activity

The phagocytic function of the retiluloendoelial system is induced by histamine as a chemical agent. Hitttmin causes endoSeHáloí bunk ^{y á} ktpil peripheral lymph glands may also in northern nt short time acquire ftgoc ^y tarian účinnooti well jtko similar cells in the nucleus, spleen or bone marrow may thus β hruootOt ntpPíkitO injected pudtnuu 'ink.

Since the chamomile releases histamine t activates the system, the efficacy of pure chamomile oil t in the inclusion complex can be inhibited by screening ryclU-Ossi, which secretes the ink, by stimulating it into the bloodstream of the test animals.

The test animals have a CFLP of 25 P 2 g (CFLP), which inhibits genetic information regarding the strains used. Meeodikt corresponds to the way that is specified in ^{the p} Ubli TCI Jtncs * of ^M: Orvos ^to Jtpjt, 1947, III, 28, 1025). 0.5 ml of 10% ink in 25 g of iron hydroxide in physiological sodium chloride solution was injected into the ocular veins. Carbon dioxide-forming suspensions with a diameter of only 0.2 to 1 μm should be used as the solution with larger particles will clog the lymph nodes in the lungs of the animal. die nt emboJii. Prior to the Indian ink injection, 0.5 ml of sodium chloride solution is administered subcutaneously. One hour before the injection of ink, the animals administered 5 mg peroráině chamomile oil and 5 mg ^{of p} ro ^d from ^p uktu Rikli in ^{the first P} tk se ^f otome torlcty sletoje removes the ink from the ^circulation .

After the administration of the ink, every 5 minutes a 10 ml blood pipette is drawn with the pipette, the blood is humous in tictiic water, and the solution is lightened photomeerically.

The ink swelling from the blood of control animals is shown in FIG. II.

Investigation of the toxicity of the chamomile ioclonal complex by β-cyclodextria showed that the complex was not toxic.

mice having a body stmicím hmoonoosi 20 TZ 25 g complex was administered as a suspension peror ^Al of ^{a c gives a 'y} VK · TZ ³⁰⁰⁰ cu ^from O ^Op OVI ^OA 234 ^g Honen ^ú l ^ Tyagi. Oyšíd STMC ^{10 of} the body 20 hmoonoosi TZ 25 g zt received similar conditions also TZ · 3,000 mg / kg, corresponding to nt 264 mg kg body hmUnosst terms of active substances can not be prokáztt no toxic přízotky. Ptk was administered 10,000 rats of 10 rats of 150 to 200 gm with a monoclonal dose of 5,000 mg / kg of hormone equivalent to 430 mg of active ingredient / kg, in which case no signs of toxicity could be detected.

Ttbulkt II

Drawing blood from the ink

(Raising ink extends the extiocation blood on average 25%, data in the trioL of indications reduction of ex- on average in groups of eight animals) Dobt after delivery of ink ^E t - ^E t t ₁ t ₂ ... 1 ΛΛ ^Eu KouOroly Chamomile ULej The product of Example 1 PO 10 to 20 oinx) 2.63 7.78 6.75 after 20 to 30 oio 3.43 3.30 5.60 After 30 to 40 mio 1, 69 5.47 4.67 After 10 to 40 oio total 8.15 16.55 17.12

See Table II:

^X) . the precision of the extinction at time 0 could not be determined

E _t extinction, measured at time t after ink injection

E _o the extinction value measured before the ink injection

Example 2

A method for producing an inclusion complex aromatics chamomile 'beta-cyclodextrin ¹⁰ g ^b eta-cyclodextrin is dissolved at temperatures of ⁰ 5 ° C 3 °% aqueous ethanol, n-EZ 2.5 g camomile tromatických substances obtained from 30 g of chamomile flowers in solution in 10 ml of ethanol. 10 to 12 minutes after the addition, the system. The mixture was no longer heated and cooled to room temperature with stirring for 4 hours. The mixture is then stored in a refrigerator for 16 hours, then filtered with a glass filter and dried with phosphorus pentoxide. In this way 10.8 g of a yellow-white crystals of the product are obtained, which contains approximately 12% by weight of the active ingredient.

The chamomile extract (Antemis ncoblis) is preferably used for the production of aromatic and fragrant substances from chamomile flowers and a complex of these substances, since this drug contains only small, but low-quality, chatataeeitticaé substances for the oil. aromatic and fragrant substances.

EXAMPLE 3

Sennzricke evaluation of chamomile tea (KsmoPeat ')

The product of Example 1 contains all of the phamolecologically important components of the camomile, but does not contain components that are chamatic and aromatic for the camomile-flavor. In most cases this is not necessary, but in some cases it is also desirable to use the scent. The product of Example 2 contains fragrances and chamomile tea can be produced by combining the two products mentioned above.

The following samples were compared: 4.5 g of the product of Example 2 (fragrance complex) + 0.5 g of the product of Example 1 (chamomile oil complex) in 1 liter of water and a sample obtained by boiling 2.2 g of chamomile flowers in 1 liter of water.

Comparisons were performed using the subjects that received the chamomile tea and ^{let alone} the ^K in TOJ with ^ ahem uvetoného tomj & exu. Patterns of tulle tempered at ²⁰ ° C, not the ^b at ⁴⁰ ° C and nádotyy samples tulle covered with paper that can not affect the outcome of the error vs ^b ieaaivní rozdíným color samples.

^The rearward soldering ennzric ^Ké ^ ovetono ¹¹ sss AOI ^{p b p} s te Lot ^{E 20} and 4 ⁰ ° C.

The identity of the tulle sample was correctly determined by 10 persons, 3 persons reported chamomile flowers tastier, 7 persons preferred tea and which tulle was prepared from the inclusion complex.

For this reason, statistical significance for the resolution of 99-9% statistical significance for determining the quality of 99.0%.

Persons who correctly separated the two types of samples at the same time preferred iati, which tulle prepared from the inclusion complex with statittiakst significance! 99.9%.

Example 4 g of the product of Example 1 corresponds to 8.40 g of air-dried drug. This product can be used in intestinal inflammations in pigs, cattle, horses, dogs and cats in the following cases:

a) In all cases where inflammation of the stomach or intestine was caused by a dietetic error. After an initial fast, 50 to 150 are administered to the animal. mg of camphor / kg body weight or the next dose in tablets 3 to 5 times daily for 2 to 3 days or until the condition is restored. Preferably, the product may be combined with treatment with activated carbon. Instead of drinking water, it is preferable to administer an aqueous solution of chamomile complex produced by the method of Example 1 heated to body temperature over an extended period of time.

b) Further, the complex may be administered in cases where gastritis or inflammation. the intestines are caused by pathogenic microorganisms (Ccoi and the like), in which case the chamomile complex is administered after administration of the laxatives together with other antibacterial agents, for example with ocoic acid. This combination is administered either in drinking water or in feed. until the animal is healed. Instead of drinking water, it is also advantageous to administer the aqueous solution of the complex until the animal is healed.

c) The complex can also be used in external inflammations in domestic animals, in particular in the form of a powder or granulate containing a complex of chamomile and cyclodeetrine, the powder or granulate being preferably applied to the inflamed skin together with the scrim just prior to application. soak in water for a short time.

d) The solution or suspension of the product of Example 1 can also be administered in the case of inflammation of connective tissue or oral mucosa, in case of formation of aphthae or irritation of the uterus.

(e) Piglets experience non-specific non-infectious inflammation of the intestinal mucosa some days after weaning with a probability of 30 to 90%. The timing and intensity of the inflammation of the intestinal mucosa can be reduced or the number of days required to cure the inflammation can be reduced by administering to the piglets a feed of camomile oil and iets-cyclic dextria produced by the method of Example 1. At the same time food and better use of feed.

3.42 kg of chamomile oil-ietS cyk-cyclsdeetrin complex prepared according to the method of Example 1 are homogeneously mixed with flour to 50 kg of spPss. This mixture is then diluted 200-times with the volume of feed to give 10,000 kg of feed, which is fed tightly to the piglets. After weaning · This food is administered at an average dose of 0.5 kg per day and contains 15 mg chamomile oil. The experiments were carried out on two separate farms on which pigs were grown on a large scale. The 28-day tetrahybrid veppi was observed on farm I and the piglets were fed a Phhyaxia feed, a dry feed that the animals could admit at will. On farm II, the same type of piglets were used, the piglets were fed with feed Scent. Otherwise the experimental conditions were exactly the same.

The following tables show that the average daily increment is significantly better in the chamomile-administered group than in the control group, moreover, the dietary feed required to obtain a 1 kg increment is simultaneously lower.

The animals were 25 to 30 g more daily, and 100 to 125 g less feed was needed to increase 1 kg.

223972 8

Farm I

Weight gain and feed utilization

Group receiving the complex Control group Age in days at the beginning of the experiment 29.56 + 4.60 25,? 0 + 2.14 at the end of the experiment 49.56 and 4.60 45.50 + 2.14 Number of animals at the beginning of the experiment 309 306 * at the end of the experiment 299 293 Number of deaths 10 (3.24%) 13 (4Í25 «) Enteritis 8 (2.59%) 12 (3.92%) Other causes 2 (0.65%) 1 (0.33%) Average weight in 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 and 1.17 Average increase in kg 6.59 5.89 Average daily increment in kg 330 295 Total feed consumption in kg 4 350 4 050 Average daily consumption feed in g 715 676 Amount of feed required to achieve an increase of 1 kg in kg 2 171 2 296

Farm II Weight gain and feed utilization Group receiving the complex Control group Age in 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 at the beginning of the experiment 234 211 at the end of the experiment 225 206 Number of deaths 9 (3.85%) 5 (2.37%) Enteritis 6 (2.56%) 3 (1.42%) Other causes 3 (1.28%) 2 (0.95 *) Average weight in 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

Farm II - continuation

Group receiving the complex Control group Average increase in kg 8.27 7.59 Average daily increment in kg 306 281 Total feed consumption in kg 4 850 4 206 Average daily fuel consumption in g 783 747 The amount of feed needed to achieve an increase of 1 kg in kg 2 556 2 658

Example 5

Powder for children

Ingredients Quantity in chamomile extract complexed with beta-cyclodextrin 5.0 g 100% azulene oil complex with beta-cyclodextrineip 5.0 g basic magnesium carbonate 70.0 g talc 920.0 g

000,0 g

The complex with camomile and azulene oil is thoroughly dusted so that the mixture can be completely passed through a 0.16 mesh sieve (Ph.Hg.VI. classification). The mixture is then mixed with magnesium carbonate and talc, and the finished powder is passed through the sieve once more and filled into the powder.

Example 6

After Shave Dry Powder

Ingredients Quantity in g chamomile extract complex with beta-cyclodextrin 5.0 100% azulene oil complex with beta-cyclodextrin 5.0 kaolin magnesium carbonate starches (ANM) cetyl alcohol magnesium stearate zinc oxide talc 130.0 130.0 116.0 20.0 30.0 50.0 514.0

000.0

The inclusion complexes of camomile extract and azulene oil with beta-cyclodextrin are thoroughly dusted, so that the mixture can be completely sieved through a 0.16 mesh screen. The active ingredient thus prepared was mixed with starches (ANM = amylum non-muclaginosum spp. For powder manufacture), then the remaining powder components were added and mixed thoroughly. Then - the mixture is forced again through the above-mentioned sieve and filled into flowing or compressed - cylindrical forms. .

Example 7

Tablets for the preparation of iaje

Ingredients Miooasví in g chamomile extract complex with ietk-cyUltdettrium 20.0 100% azelate oil complex with ietk-cyUltdettrie 20.0 ^ korbic acid . 44.0 miiiaen sodium 15.0 glycerin stearate 1.0

Ascorbic acid and sodium hydrogencarbonate together with glycerine monnotearate are processed to granules according to conventional technology. The mixture of camomile extract and azulene oil with beta-cyclodextria is thoroughly powdered so that the mixture passes through a sieve of 0.16 mm mesh without residue (Ph.HeVI · sieve classification). Using the camomile extract and azulene oil-beta-cyclodextrin oil complexes, the ascorbic acid and sodium hydrogencarbonate granules were mixed and compressed to give tablets of about 0.5 g.

Example 8 i ^ea

For the production of tea, the individual components are used in the following ratio:

1.8 g of chamomile drug extract with i-κ-cyclodettriae and 0.2 g of chamomile oil beta-cyclodextrin complex are dissolved in 100 ml of hot water.

Claims (4)

CLAIMS 1. A process for the preparation of a medicament comprising cyclodeetrin-camomile complexes comprising reacting an alpha, beta or a mixture of these substances in the form of a solution with an extract derived from a camomile drug known from the prior art. z ^ together at a temperature ^of 15 to ⁸⁰ ° C, preferably 5 ° ^C and REA ^ it was ^p omal cooled with vigorous míсИ ^ пП »thus obtained ííUIuzíí complex of reakiní cyanoformate is isolated and then together with a carrier, p ^ the pharmaceuticals, flavoring agents, lubricants, glidants, and optionally other ingredients, to form a medicament. 2. A method according to claim 1, wherein the extract is prepared from Flores chlum and / or Anthemis notHis and / or Amino. 3. A method as claimed in claim 1, wherein a blue oil prepared from a camomile drug is used. 4. A process according to claims 1 and 2, characterized in that an extract of fragrances and / or flavorings prepared from the camomile drug is used.