SE436831B - PROCEDURE FOR THE PREPARATION OF PHARMACEUTICAL FORM FOR ORAL ADMINISTRATION - Google Patents

Description

vs0vu1z-en l0 1.15 20 25 30 35 35 _ 2 'of powdery mildew alkaloids, such as Kdihydroergotoxin, dihydroergocristine, dihydroergocorin,' dihydroergocryptime 'dihydroergotamim dihydroergonin, dihydroergovalin, i' ergolan, aetc.

The content of active substance in the new forms of prescription can of course vary greatly. Prior to achieving a particular therapeutic result, the amount of active substance applied per dose may be lower in the pharmaceutical forms of the invention than the amount of active substance required to achieve a similar result in a hitherto conventional composition. The 'active substance' content may vary, for example, with regard to the nature of the "active substance" used, the condition to be treated and the chosen pharmaceutical form, and may be in the case of single-dose, particularly solid administration forms. to 5 and in liquid administration forms up to 9 g / l in the composition. Thus, the content of active substance in droplet solutions may preferably be between 0.05 and CO 2, 696 and in tablets, capsules, etc., preferably between 0.2 and ~ 1 +, 0, especially between 0.2 and 2.596.

Physiologically acceptable emulsifiers are preferably used - which have an average HLB value of 12f-20, especially 12-16, or mixtures of emulsifiers with high and low HLB values, which together give an average l-1LB value. of preferably 12-20, especially 112-16. For the preparation of solid pharmaceutical forms, such emulsifiers or emulsifier mixtures which are solid at room temperature. However, the chemical and physical properties, molecular size and shape of the hard-to-absorb pharmacologically active components used and the other, if any, co-formulants which may be involved in the formation of aggregates prove to be particularly suitable. _ _ "Ethoxylated cholesterol" as used herein refers to various compounds "obtained" in the ethoxylation of cholesterol depending on the amount of ethylene oxide used per imo! cholesterol. One can e.g. use ethoxylated cholesterol with about 24 moles of ethylene oxide _ I per mole of cholesterol, e.g. the commercial product Solulan C 20 from American. "Cholesterol Co.

The amounts of emulsifiers used may vary with the nature of the emulsifiers, in particular their chemical and physical properties, the nature and amount of any excipients, the nature of the active substances used and the extent of the desired resorption enhancement. The upper limit of the amount of emulsifier added is of course governed by the physiological acceptability of the emulsifiers in question, possibly taking into account the intended treatment time and frequency of application. However, the individual ingredients are present in the new pharmaceutical forms, preferably in such amounts that the 'total amount of physiologically acceptable' emulsifiers does not exceed 50 mg / single dose. The ratio between the total amount of emulsifier and the amount of active substances is, for example, 10: 1-50: 1, preferably 20: 1-30: 1. In anhydrous formulations, the total amount of emulsifier may be up to 60%, as in single-dose administration forms preferably between 20 and 50%. In aqueous formulations, the emulsifier concentration is between CMC and MAC for the emulsifiers used (CMC = critical micelle concentration, MAC = maximum additive concentration). The total amount of emulsifier in aqueous administration forms is preferably 1-596.

The pharmaceutical forms may optionally contain lipoid carrier materials resp. carrier material in an amount up to 25 times, preferably up to 10 times the amount of active substance added. As lipoid carrier materials it is possible to use, for example, wholly or partly with higher aliphatic carboxylic acids esterified mono- or polyhydric lower alcohols, preferably alcohols having 2-3 carbon atoms, in particular glycerol or propylene glycol, or condensates thereof, such as polyglycerol. For the preparation of solid pharmaceutical forms, solid, lipoid carrier materials are preferably used at room temperature, and for the preparation of liquid pharmaceutical forms, liquid, lipoid carrier materials or at room temperature liquid mixtures of solid and / or liquid lipoid carrier materials are preferably used. As solid lipoid carriers, only partially esterified alcohols, especially saturated mono- and diglycerides, can be preferably used. The aliphatic carboxylic acids present in the solid esters may preferably contain 12-20 carbon atoms and may be straight or branched and / or hydroxylated. For the preparation of liquid pharmaceuticals, it is particularly convenient to use fully esterified alcohols, especially triglycerides, for example esters of unsaturated carboxylic acids or saturated carboxylic acids having preferably 8 to about 12 carbon atoms. Examples of suitable esters are bLa. mono-, di- or triglycerides of saturated or unsaturated fatty acids, such as glycerol monolaurate, myristate, oleate or ricenolate, peanut oil, oily triglyceride mixtures of saturated plant fatty acids having 8 to 12 carbon atoms or propylene glycol esters such as propylene glycol esters.

The new pharmaceutical forms may further contain physiologically acceptable pharmaceutical excipients customary for the manufacture of solid and liquid pharmaceutical forms, provided that these do not impede the formation of the substance- and emulsifier-containing aggregates or adversely affect the stability of the aggregates formed.

It has also been found to be advantageous to add water-soluble solid or liquid, physiologically acceptable mono- or polyhydric alcohols. Suitable alcohols are, for example, ethanol, propylene glycol, glycerol, sugar alcohols and polyethylene glycols having an average molecular weight of, for example, 300-10,000. R 1507413-a 4 A for the solubilization of the water-soluble active substances * K-promoting additive a_Kv polyalcohols, especially polyethylene glycols, is particularly desirable. For the preparation of liquid dosage forms, K liquid alcohols are preferably used, for example lower mono- or polyhydric alcohols and / or K polyethylene glycols having average molecular weights below 2,000, preferably between 300 and 1,500. For solid pharmaceutical forms, solid alcohols are suitably used at room temperature, for example strong alcohols and / or prylctyl glycols with average molecular weights above 1,800, K preferably between 2,000 and 10,000, especially 5,000-7,000. A particularly suitable embodiment of the invention constitutes liquid or preferably solid galenic formulations, wherein the total amount of polyalcohols, and emulsifiers in aqueous formulations preferably constitute between 15 and 8096 of the total composition and in anhydrous formulations between 40 and 9996 of the total composition. _ K ~. The polyalcohols and emulsifiers comprising the portion of the composition K may be composed of Ken or several non-emulsifying polyalcohols, preferably polyethylene glycols, and one or more ethoxylated cholesterol. A particularly suitable combination has been found to consist of ethoxylated cholesterol Koch f polyethylene glycols and / or. polyoxyethylene polyoxypropylene polymers. The dewatering drug forms of the invention may contain, for example, K between 20 and 95, preferably between 30 and 70 weight-96 water and any additional excipients. Alcohol- resp. The polyol content of the aqueous liquid may be, for example, 0-50, preferably 20-40% by weight of the composition. _ K _. K 25 K r - Anhydrous, liquid formulations contain active substance and emulsifier-containing aggregates, which are extremely finely divided in a water-soluble and / or in a water-dispersible, liquid carrier material of KenKeller several carrier components and possibly additional excipients. As the effluent carrier material, it is particularly convenient to use Physiologically acceptable, lower; mono- or polyhydric alcohols and / or liquid polyethylene glycols, such as K polyethylene glycols having K average molecular weights below 2,000. KK As additional ingredients, the liquid pharmaceutical forms may optionally be supplemented with additional pharmaceutical excipients, such as preservatives, flavoring substances, buffering substances, etc. The liquid preparations, especially if further processed into solid dosage forms, "contain further aqueous physiologically useful substances. and / or in water dispersible solids KKK The solid pharmaceutical forms according to the invention contain the active substance and emulsifier-containing aggregate in extremely finely divided form in a carrier material formed from one or more carriers. water-soluble and / or water-dispersible solids and any additional pharmaceutical excipients.

As physiologically acceptable water-soluble solids, it is particularly convenient to use at room temperature solid polyethylene glycols, preferably polyethylene glycols having an average molecular weight of between 2,000 and 10,000, especially between 6,000 and 10,000, polyvinylpyrrolidones, solid oxyethyleneoxypropylene polymers, sugar alcohols, such as mannitol or sorbitol, carboxymethylcellulose, etc.

Water-dispersible solids are preferably added in the form of finely dispersed powders, which due to their large surface area are capable of adsorbing active substance and emulsifier-containing aggregates in an extremely fine state.

Suitable solids are, for example, physiologically acceptable, water-dispersible, non-swelling inorganic and / or organic carriers, unless they bind the added active substances irreversibly. Suitable inorganic carriers are, for example, dicalcium phosphates or highly dispersed silicic acids, the shaking volumes of which are preferably between 250 and 1,000 ml / 100 g, especially in the wet state of precipitated silicic acid.

As additional ingredients, the solid pharmaceutical forms may, depending on the composition selected, contain additional physiologically acceptable pharmaceutical excipients, for example, preservatives, flavoring agents and, in tablet manufacture, suitable conventional tableting excipients.

The active substance-containing aggregates present in the new pharmaceutical forms can have a diameter of up to 20,000 Å, preferably between 10 and 100 Å, especially below 200 Å.

In wet drug forms, the distribution of the emulsifier and active substance-containing aggregates in the aqueous liquid is preferably so fine that transparent or weakly opalescent liquids are obtained. The diameter of the active substance and emulsifier-containing aggregates is preferably below 2,000, in particular below 1,000 Å.

The anhydrous solid and liquid pharmaceutical forms obtained according to the invention consist of dry resp. liquid preparations, which preferably contain the active substance-containing aggregates in such a finely divided form that in water medium they rapidly give a transparent or weakly opalescent liquid, wherein the difficult-to-absorb active substance or substances are solubilized in the form of extremely atomized active substance- and emulsifier-containing aggregates.

The novel drug forms of the invention may be liquid or solid and are preferably administered orally. The liquid preparations can be administered, for example, in the form of a droplet solution, syrup, etc. Anhydrous liquids can also be applied in soft gelatin capsules to produce single-dose administration forms. Among aqueous forms of administration, drip solutions are most suitable. Suitable fixed forms of administration are ï i.a. powders, granules, capsules, tablets or film tablets for oral administration. The process according to the invention is preferably carried out by dispersing the difficult-to-absorb pharmacologically active substances and emulsifiers, optionally with the addition of additional pharmaceutical aids, in the liquid carrier materials, for example in an anhydrous medium or in water or an aqueous medium, using ultrasonic and / or high speed tube stirrers. According to one embodiment of the process, for example, first with gentle heating, the difficult-to-absorb active substances can be dissolved in the emulsifiers, optionally with the addition of lipoid carrier materials, and then during ultrasonic treatment or in high speed mixers diluting this mixture with liquid carrier material and at the same time homogenize it.

According to the invention, the preparation of the new solid pharmaceutical forms can be carried out by gently removing the liquid carrier materials, such as water and / or lower alcohols, from the primarily prepared liquid preparations and transferring the obtained powdery or spongy porous dry preparations to per se known method to a desired form of administration.

The gentle drying can be carried out in a manner known per se, for example by freeze-drying or spray-drying. Thus, for example, the liquid preparations can be frozen at a temperature between -80 DEG and -80 DEG C. and then lyophilized in a high vacuum. The liquid preparations can also be transferred to a mist in a drying room, after which it is dried with a hot stream of air, 'for example' at a temperature 'of 120-180 ° C. The resulting dry preparations can then optionally be further processed in a manner known per se, for example with the addition of additional suitable pharmaceutical excipients, such as tablet excipients, etc., such as being filled into capsules, granulated, or tableted. The invention is further illustrated by the following examples, in which the indicated temperatures refer to Celsius degrees. Aqueous droplet solutions of difficult to absorb. active substances The compositions of Examples 1 to 17 having the composition given in the following Table 1 are prepared as follows; The sparingly resorbable active substances are dissolved under gentle heating (at temperatures between 30 and 500) in the emulsifiers and any lipoidic carrier materials and optionally with the addition of a portion of the polyalcohol.

This solution is stirred vigorously with a Polytron brand homogenizer, slowly with the water or an aqueous solution of any additional excipients or a mixture of water and any polyalcohols, after which the resulting mixture is homogenized for 5-6 minutes by sonication and / or the homogenizer.

The homogeneous liquids obtained are filled into drip boxes.

The reference letters in Table 1 after some of the components refer to the following commercial products used in the experiments according to the examples (the composition of the commercial products is given in Table 1): a) Solulan C Zig from Fa. American Cholesterol Comp. b) Miglyol 8IZ® "Fa. Henkel c) Tegomuls 70" Fa. Goldschmidt AG d) Silica K32O (shaking volume approx. 500 ml / 100 g), Degussa 7507413-82 Table 1 Aqueous droplet solutions Example no. 1 2 3 40 mgf active substance:.

Dihydroergocristine Dihydroergovalin Dihydroergotoxin 7 Di hydroergocornin _ Dihydroergocryptine I Ergotamine ~ d, IB-bromodihydroergotamine IB-bromodihydroergocryptine 360 4.00 800 800 800 800 g emulsifiers: with ung. 24 moles of ethylene oxide Ethoxylated cholesterol a) 3.6 4.0 8.0 8.0 I g lipoid carrier material: liquid triglyceride of saturated fatty acids having 8 to 12 carbon atoms b) Glycerol monolaurate Glycerol monostearate palmitate c) Glycerol monoricenolate Glycerol glycol monoleate Glycerol monisostearate 0.9 2.0 1.8 3.5 g Additional auxiliaries: Polyethylene glycol 300 Polyethylene glycol uoo Polyethylene glycol 600 Polyethylene glycol l500 Polyethylene glycol 2000 Glycerol 20 16 10 _40 # 0 5.5 I 40 "Vatfcen 20 15 29, 5 50.7 34 , 2 54,2 '75071413-8 9 Table 1 (continued) Aqueous droplets Example No. 7 8 9 10 11 12 13 mg active substance: Dihydroergocrystine 400 400 # 00 200 200 800 200 Dihydroergovalin Dihydroergotoxin Dihydroergocornine Dihydroergocryptine Ergotamine IB-bromodihydroergotamine lB -bromodihydroergocryptine g emulsifiers: with approx. 21+ moles of ethylene oxide 10 6 6 3 3 8 2.5 Ethoxylated cholesterol a) g lipoid carrier material: liquid triflyceride of saturated fatty acids with 8-12 carbon atoms b) Glycerol monolaurate 2 Glycerol monostearate palmitate c) Glycerol monoricenolate 2 Glycerol monooleate l Propylene glycol munostearate l Glycerol monomyristate l Glycerol monisostearate 0.5 g Additional excipients: Polyethylene glycol 300 Polyethylene glycol glycol 400 Polyethylene 400 Polyethylene 95.8 53.2 96.8 'rsovlmz-a É 10 _' Table 1 (fm-ts.) A Aqueous droplet solutions eßxempexnf. í e 14 15 le V 17 mg active substance: Dihydroergokfisrin zoo Díhydroergonin _ _ A. _ 600 Dihydroergocryptin _ Dihydroergocryptí fi Ergotamine '13-bromodi fihydroergotamine ~ - _ 120 1B-briodomdihydroergocryptine Dihydroergotamine _' "_" ~ 'v300 g erhulgators: with young, 2 !! moles of ethylene oxide 3 57.8 6 »3 ethoxylated carbonaceous a) V g lipoid carrier materials: liquid tri fl yceride of saturated fatty acids of 8-12 7 colloids b) _ _ -7 3,5 'Glycerol monlaurate Glycerol monostearate β palmitate monorate C)> Glycerol . Glycerol monooleate Propylene glycol monostearate Glycerol monomyristate.

Glycerol monisostearate. g additional aids; Polyethylene Glycol 400 V f _ 30 Polyethylene Glycol 60AO 'I Polyethylene Glycol 1500' Polyethylene Glycox 2ooo__ Glycefol eae Polyethylene Glycol130O 45 I '47 u * I> 25 j, Water' 46 * f '477: so * ao * x with sodium acetate / acetic acid mixture -acetic acid pH 18-, 3.r 10 15 20 25 30 35 '7507413-8 11 Example 18 Dihydroergotamine-containing drip solution 60 mg of dihydroergotamine mesylate and 1.5 g with approximately 21+ moles of ethylene oxide ethoxylated cholesterol a) are immersed in 60 ml of water, which with sodium acetate / acetic acid buffer mixture is adjusted to pI-1 14.1, and homogenized with a Polytron brand homogenizer. The clear liquid is filled into small dropper bottles.

Example 19 Dihydroergotamine-containing anhydrous droplets (a) 2 g of dihydroergotamine and 50 g with about 21 g! mol of ethylene oxide ethoxylated cholesterolh) in 500 g of polyethylene glycol 1:00 is lowered under heating to 500 on a water bath and treated for five minutes with ultrasound and the clear liquid is filled into droplets. (b) The experiment according to (a) is repeated, but using instead of 50 g of polyethylene glycol 400 a mixture of 250 g of polyethylene glycol 1:00 and 250 g of glycerol.

Example 20 Dihydroergonin-containing soft gelatin capsules In 3 g of dihydroergonin and 75 g with approximately 21+ moles of ethylene oxide (ethoxylated cholesterol) are lowered while heating on a water bath to 50 ° and sonication in 150 ml of polyethylene glycol 300. The clear liquid is then filled into soft gelatin capsules. 100 mg / capsule.

Example 21 Dihydroergocristine-containing capsules 300 mg of dihydroergocristine are dissolved together with 1.7 g with about 21+ moles of ethylene oxide (ethoxylated cholesterol) and 1.2 g of glycerol monolaurate with heating to 400 and homogenized with the addition of 30 g of a 2296 g solution of oxyethylene oxypropylene polymers with a average molecular weight of 8,700 in water. After dilution with 50 ml of water, the material is frozen in a rotating flask rapidly at -80 °. after which it is lyophilized in a high vacuum. With progressive lyophilization, the dry material is eventually heated to 25-30 °.

The resulting dry preparation is then filled in an amount of 50 mg / capsule into capsules.

Example 22 Dihydroergotamine-containing capsules 30 mg of dihydroergotamine are dissolved together with 750 mg with approximately 21+ moles of ethylene oxide ethoxylated cholesterol in 50 ml of absolute ethanol and the solution is evaporated to dryness in vacuo at 300. The residue is homogenized with gradual addition of 100 ml of distilled water with a brand homogenizer Polytron for about five minutes. In the resulting clear liquid, 225 mg of 10 015 was suspended. In a 12 g of highly dispersed silica, the suspension is homogenized by sonication for three minutes at 30 °. The suspension is frozen at -800 and then lyophilized. The lyolate is filled into gelatin capsules in an amount of 100 mg / capsule.

Example 23 Dihydroergovalin-containing lyophilizate in dry ampoules I - # 00 mg of dihydroergovalin are dissolved together with 10 g with about 24 moles of ethylene oxide (ethoxylated cholesterol) and 11-0 g of polyethylene glycol 2000 in 300 ml of absolute ethanol. The solution is evaporated on a rotary evaporator at 300 to dryness. The residue is slowly stirred with the Polytron brand homogenizer slowly with 200 ml of distilled water. The clear, micellar solution of the active component is filled into ampoule ashtrays (2 mg dihydroergovalin per unit) and the bottles are rapidly frozen at -8 ° C. Analyzed with Examples 21-23, dry preparations can also be prepared with the composition given in Table 2, which are filled into capsules or dry ampoules or granulated and / or tableted with the addition of suitable galenic auxiliaries.

The reference letters in Table Ziefter some of the components refer to the following commercial products (the composition of which is given in Table 2): a) Solulan C 24, American Cholesterol Comp. d) Silica K320. (shake volume approx. 500 ml / 1.00 g), Degussa _ e) Solulan Cl. , and American Cholesterol Comp. f) PvP Kao .ßadische Annm- und sodafabrik g) Primojeß, Badisçhe 'Anilin- und Sodafabrik 7507413-8 13 2 oN o * 2 oN oon om S oN som wn NN ON Aw .mmßzszvut fi ucbxonïmm wowxmq G coed: wvïšc: ocv ïcv -.mvzß: u mš fl w fl x mhwmm fi v om 2 o: ON Nån C02: _ .. v_šw = @. b @ b ° m 88 _ov_.sw = .. zà, 9som 88 _ ° v_: w = ~ _à2: ° m fl ovvEa fi mmn vhmw fl hupï w u fl smïcoëïäušü »m« &. šEocoE_o..wu> Ü: fi håmåhmhwn mBoa: m om n: nn nu ow om Û WN mn Na nu o ..

ON Ü Éhuvmø fl ox vmhvšxopu wmxocøfåø BE 2 .was vvE An Éhowwnåox wmhmšxoww Exocoz fi w .QE ä .was uwE "uøhowmw fl sëu w io wá .hEmvowhvoh fi šcm ow mm Zw mx fl cm fi cs. N: ønmh 27507413-sgi ll) The following Table 3 shows that the dihydroergotamine concentration in body fluids 'increases after oral' administration if the active substance is supplied together with ethoxylated cholesterol (emulsifier Solulan C24) according to the invention. The part of the dihydroergotamine precipitated in urine and bile is determined by the radioactivity measurement method, shows that those lecithins often used as emulsifiers (cf. DEf-Al 083 985) do not give any advantages over the standard (without the use of an emulsifier). addition of ethoxylated cholesterol (Solulan C211) to 3- to G-fold increase of the resorbed proportion. in the breed 3 "nmYoRoERGot / (Mxni Dose of in emulsifier rat 96 bile 96 urine" 96 total g condition ard 5 _ i 5.01 _ 1.35 i 6.37 (without emulsifier) (f 1.36) (f 0.710 (i 0.76) Lecithins: _ g Palmitoyl-propanediol- (1,3) - 25 mg 5.90 1.83 7.73 fostofyiknlin g. (f 2.27) (f 2.18) (f 0.76) g Parminny-popanediol- (1,3) - 25 mg 5.56 1.13 6.69 fosioric acid propyl ester g (f 0.914) ( f 0.35) (f 0.88) Paimitoyl-LZ-dimethylpro- 25 mg g 4.85 1.59 6.1 + 4 d1n1 ~ (1,3) -phenoic acid _ _ g (f 2.01). (f 1.27); (f 1.07) (i propylene glycoDx gii sniuian c 24 a) '5 mg g 116.41 2.45 g 18.86 (1 M1g1yn1 b)) * gi' (f 4.40) (f 1.29) (f 4.81) sqxuxan c 24 É) 25 mg. 29.81 i 4.68 34.49 (i spruce * _ (f 3.88) (f 2.22) (f 2.74) smulan c 24 a) gf 50 mg 21.58 3.56 25.14 (1 1v11g1y01 b)) “iggg (f 4.00) g (f 2.60) (f 2.80) s61u1an c 2473) 7 50 mg 30.77 3.41 34.19 (fl mnnnn * _ g _ i (f 9.22) (f 0.91) (f 9.19) s61ng1an c 24 a) i 50 mg g 23.60 2.33 25.93 (1pfnpy1eng1yko1) * gig (f 5.29) (f 0.91) in (f 5.73) - x the solvents indicated in parentheses were used instead of water. 7507413-8 15 a) Solulan C 24 = about 1 mole of cholesterol ethoxylated with about 24 moles of ethylene oxide (Amer.

Cholesterol Co.) b) Miglyol = liquid triglyceride of saturated fatty acids with 8-12 carbon atoms (Henkel).

Table 4 Comparison with the composition according to DE-A1 617 822 regarding resorption of dihydroergonin in rats (5 animals) Resorption (0 - 48 h) (= excretion with bile + urine) Composition 96 bile 96 urine 96 total A) 0.5 mg dihydroergonin 0.6 mg HPT l3 4 17 10.0 mg Klucel EB) 0.25 mg dihydroergonin 0.3 mg HPT lll- 3 17 5.0 mg PvP C) 0.05 mg dihydroergonin 50.0 mg Solulan C 24 (i ethanol) 52 5 57 500.0 mg polyalkylene glycol 300 D) 0.05 mg dihydroergonine 50.0 mg Solulan C 21+ (in ethanol) 51+ 4 58 400.0 mg Z-propylene glycol 100.0 mg glycerol HPT = hydroxypropylethylene Klucel E = hydroxypropylcellulose (Hercules) PVP K 30 = polyvinylpyrrolidone = Collidone 30 (BASF) Solulan C 24 - about 1 mole of cholesterol ethoxylated with about Z1; moles of ethylene oxide

Claims (2)

1. e rvtslovm-s ä 10 15 20 25 30 16 PATENTKRAV ll. Process for the preparation of new pharmaceutical forms for oral administration, characterized in that pharmaceutical forms containing aggregates with a diameter not exceeding 20,000 Å, consisting of: 1 a) a sufficient amount of powdery mildew alkaloids for synthetic purposes or synthetic or semi-synthetic lysergic acid derivatives' and b) one or more pharmaceutically acceptable emulsifiers in the form of ethoxylated cholesterol having an average HLB value of 10-30, wherein the emulsifiers are present in an amount of at least ten times the weight of the active component, by dispersing the components mentioned under (a) and (b) in a liquid carrier, optionally with the addition, of additional pharmaceutical excipients, and then optionally removing the liquid carriers from the dispersions obtained. 2. A process according to claim 1, characterized in that "as components according to (a) ergotamine, dihydroergotoxin, dihydroergocristine, dihydroergocornine, dihydroergocryptine, dihydroergotamine, dihydroergonine or dihydroergovalin are used. according to claim 1, characterized in that any of the components according to (b) use an ethoxylated cholesterol, wherein 1 mole of cholesterol is ethoxylated with 24 moles of ethylene oxide - The process according to claim 1 is characterized in that the aggregates containing the active components have a * diameter below 2000 Å. A process according to claim 1, characterized in that one first dissolves the component mentioned under (a) in component (b), possibly during addition gave lipoid carriers, and then disperses them in A process according to claim 1 or 5, characterized in that an anhydrous medium, an aqueous medium is used as the liquid carrier m or water. 7507413-8 17 7. A method according to claim 1 or 5, characterized in that the dispersion is carried out by means of ultrasound and / or high-speed stirrers. 8.7. A method according to claim 1, characterized in that the removal of the liquid carriers is carried out by freeze-drying or spray-drying.