CA1057196A - Pharmaceutical compositions - Google Patents

Abstract

IMPROVEMENTS IN OR RELATING TO ORGANIC COMPOUNDS

Abstract of the Invention This invention relates to a pharmaceutical composition comprising aggregates of diameter of at most 20,000 .ANG., comprising component a) an ergot alkaloid, and component b) a pharmaceutically acceptable ethoxylated cholesterin emulsifier having an HLB value of from 10 to 30 and present in an amount greater than 10 times by weight of the ergot alkaloid.
The composition has enhanced resorption properties.

Description

~OS7196 PHARMA OE UTICAL COMPOSITIONS
-` ~ The present invention relates to a pharmaceutical composition comprising aggregates of diameter of at most 20,000 A, comprising:- component a) comprising at least one pharmaceutically acceptable active agent, and component b) comprising at least one pharmaceutically ac~eptable emulsifier, component b) having a mean HLs value of 10 to 30 and present in an amount greater than 10 times by weight of component a).
More particularly, the present inventioniresides in a pharmaceutical comprising aggregates of diameter of at most 20,000 A, comp~ising component a) an ergot alkaloid, and component b) a pharmaceutically acceptable ~thoxylated cholesterin emulsifier having an HLB value of from 10 to 30 and present in an amount greater than 10 times by weight of the ergot alkaloid.
Component a) is preferably an active agent which is difficultly absorbable into the bloodstream on enteral, e.g.
oral, administration. Such difficultly absorbable active agents are those which are absorbed by the body at a cumulative percentage absorption up to 45% at most, e.g. in amounts below 35~i or even below 25% as indicated by standard tests. For example, in one test material is administered p.o. in a ca. 0.008%
w/v aqueous solution to the bile fistula rat. The cumulative percentage elimination of material in the bile and in the urine is measured in conventional manner.

~057196 The dose of material admininistered is chosen such that the cumul~tive percentage absorption substantially levels out after 48 hours. In the same test the initial rate of elimination of -aterial in e.g. the bile is also determined in conventional manner.
me present composition exhibits enhanced resorption properties as indicated in standard tests, e.g. by a greater cumulative percentage absorption and initial rate of absorption in the above-indicated test than would be expected for such 1~ compositions.
m e present compositions are therefore indicated for use with active agents for the treatment of migraine or hypertension or possibly analgesic or antibiotics, when it is desired to obtain high blood level values in the bloodstream as rapidly as possible.
Examples of component a) include nitrogen-containing compounds, i.e. high molecular, especially heterocyclic compounds, e.g. lysergic acid derivatives, alkaloids such as ergot alkaloids or synthetic or semisynthetic alkaloid derivatives, e.g. ergolene.
Preferred examples are e.g. ergotamine or synthetic of semi-synthetic lysergic acid derivatives, e.g. hydrogenated derivatives of ergot alkaloids, e.g.

~-2--.~

~. :

dihyd.roergotoxine, dihydroergocristine and the 13-bromoderiva~ive therPof, dihydroergonine, di-hydroergocryptine, dihydroergotamine and the 13-bromo derivative thereo., dihydroergocornine and dihydro-ergovaline.
Other examples include low molecular weightcompounds such as dopamine derivatives such as dopamine double molecule derivatives.
An example of a dopamine derivative is N,N'-, 10 (2-methyl-4,5-dihydroxyphenethyl)hexan~Rthylenediamine, or N,N'-Bi 5 [ 6-[(3,4-hydroxyphenyl~ethylamino]hexyl]
hexamethylene diamine.
The active agent content may naturally vary considerably and may be adjusted to the desired close depending on the type of active agents used and the condition to be treated, the. amount to be admlnistered per unit dose ~nd the type of composition.
However, in order to obta.in a specific thera-peutic result, the amount of actlve agent aclminlstered per dose in the compositlon of the invention may be smaller than the amount of the same active agent in one of the hitherto used formulations requlred for the obtention of an equal result. In the case of 5ingle dosage form, component a), may amoun~ up to 5% e.g.
up to 2.5% by weight in the case of solid preparalions and in the case of li~uid preparations ~057196 up to 1 ~ by weight of the composition. For example, component a~ in drop solutions preferably amounts to between 0.05 % and 0.6 % and in tablets and capsules preferably between 0.2 ~ and 4.0 ~, especially 0.2 and 2.5 ~, e.g. from 0.4 to 2.5 ~.
H.L.B. value (hydrophilic/lipophilic balance) of component b) is a measure for the relative portion of hydrophilic groups in an emulsifier molecule [see Pharm.~ct.Helv. 44, 9 (1969) and H.P. Fiedler, Lexikon der Hilfsstoffe f~r Pharmazie, Kosmetik und angrenzencle Gebiete, page 263, Edicio Cantor KG. 1971J.
It is preferred to use one or more physio-logically tolerable emulsifiers having a rnean H.L.B.
value of 10 to 20, especially 12 to 16. For the production of solid compositions it is preferred to use emulsifiers or emulsifier mixtures which are solid at room temperature. Examples of sui.table physioloc3ically tolerable emulsifiers of the group of the non-ionoyenic tensides are the tensides of the type of the polyol fatty acid esters or the polyol ethers with higher aliphatic or cyclic alcohols or polyalcohols having emulsifyincJ properties such as polymerization products from ethylene oxide and propylene oxide or propylene ~lycol. ~xamples of suitable polyol fatty acid esters are irter _lla polyethyler.e glycol sorbitan fatty - - 5 - iOO-4195 ~057196 acid esters, e.g. polyoxyethylene-4--sorbitan mono-stearate, such as Tween ~ 61 (Atlas Chemical Industries), polyethylene glycol fatty acid esters, e.g. polyoxyethylene-10-stearate such as Myr~ ~ 52 ~Atlas Chemical Industries), polyethylene glycol-400-stearate DAB7, polyoxyethylene glyco3 glycerin fatty acid esters, e.g. polyoxyethylene castor oil, such as Cremophor ~ EL (Bad. Anilin u. Sodafabrik). Examples of suitable polyol ethers of higher alcohols are ~nter alia polyol ethers of higher fatty alcohols, e.g.
polyoxyethylene-20-cetylic ether, such as Brij ~ 56 ~Atlas Chemical Industries), ethoxylated wool fat alcohols (e.g. with 16 mols of ethylene oxide, such as Solulan ~ 16 (American Cholesterol Comp.) or polyo]s etherified with cholesterin, e.g. cholesterin ethoxylated with approximately 24 mols of ethylene oxide, such as Solulan ~ C 29 ( American Cholesterol Comp~).
Suit~ble oxy-ethylenoxy-prc)pylene polvmerixation products are, for example, polymerization products having a mean molecular weight of approximately 1000 to 10000, e.g. an oxy ethylenoxy-propylene polymer containing 40 ~ of polyoxyethylene and having a mean molecular weight of approximately 2900, such as Pluronic ~ L 64 (Wyandotte Chemicals), an oxy-ethylenoxy-propylene polymer having a m2an molecu]ar weigh-t of approximately 3500, such as ~ ronic ~ P 65 (Wyandotte Chemicals) - 6 100-~195 or an oxy-ethylenoxy-propylene polymer containing 80 % of polyoxyethylene and having a mean molecular weight of approximately 8700, such as Pluronic ~ F 68 (Wyandotte Chemicals). The alkyl groups in the dialkyl-sulpho-succinates may contain from 4 to 10 carbon atoms.
A suitable salt isan alkali metal salt, e.g. sodium.
A preferred example of a dialkyl-sulphosuccinate is sodium dioctyl sulphosuccinate, such as ~erosol ~ OT
(American Cyanamid Co.).

It may be convenient to use different types o~ emulsifiers depending on the chemical and physical properties, molecule size and form of the component a) used and component c), mentioned hereafter.

When ergot alkaloids or synthetic or semi-synthetic lysergic acid derivatives are used, then it is particularly convenient to use polyoJs etheri~iccl with cholesterin, e.g. chol~8terin ethoxyla~ed with about 24 mols o~ etllylelle oxide It is also convenient to u~e oxy-ethyleno~:y-propylene polymers, e.g. Pluronic ~ IJ 64 or Pluronic ~ P 65 or emulsifier mixtures containing oxy-ethylenoxy-propylene polymers.
Also sui~able are polyethylene glycol fatty acid esters, e.g. polyG~:yethylene-40-steara'e or polyethylene glycol-400-stearate DAB7.

The amounts of emulsifier to be used may vary depending on the emulsifier used, especially i~s chemical and physical properties, the type and amount of adjuvants used, the type of active agents used and the desired extent of imprGvement in resorption. The upper limit of the amount of emulsifier to be used will natu-rally depend on the physiological tolerability of said emulsifier, taking into consideration the planned dura-tion of treatment and frequency of administration. The -components in the composition are preferably present in such amounts that the total amount of component b) does not exceed 50 mg/unit dose. The ratio of total amount of component b) to component a) may, for example, be fxom 10:1 to 50:1, preferably 20:1 to 30:1. In anhydrous administration forms, the total quantity of emulsifier may amount to 60~, e.g. in unit-dose preparations preferably between 20% and 50%. In water-containing compositions, the concentration of component b) conveniently is between the critical micelle concentration (CMC) and maximal addition concentration (MAC) of the emulsifiers used. The total amount of component b) in water-containing administration forms preferably is between 1~ and 5~.
The aygregates may convenientl~ contain as 25 component c) a furthex pharmaceutical carrier, prefera-. ~0571~6 - 8 - 100-4195 bly a lipoid carrier. Component c) is preferably present in an amount 25 times or especially up to 10 times the amount of component a) present.
Lipoid carrier materials which may be used are, for example, monovalent or polyvalent lower alcohols partially or completely esterified with higher aliphatic carboxylic acids, preferably alcohols of 2-3 carbon atoms, especially glycerin or propylen~ glycol, or condensates thereof, e.g. polyglycerins. For the production of solid compositions it is convenient to use lipoid carrier materials which are solid at room temperature, and for the production of liquid medicinal preparations liquid lipoid carrier materials or mixtures of solid and/or liquid lipoid carrier materials which are liquid at room temperature. Especially suitable solid lipoid carrier materials are only partially esterified alcohols, especially saturated monoglycerides and diglycerides.
The aliphatic carboxylic acids contained ln the solid esters may preferably contain 12 to 20 carbon atoms and may be straight chain or branched and/or hydroxylated.
Especially suite.d for the production of liquid medicinal preparations are completely esterified alcohols, especial-ly triglycerides, e.g. esters of unsaturated carboxylic acids or saturated carboxylic acids, preferably contain-ing 8 to about 12 carbon atoms. Examples of suitable lOS7196 - 9 - 100-4195 esters are inte~ alia monoglycerides, diglycerides or triglycerides of saturated orunsaturated fatty acids, e.g. glycerin monolaurate, monomyristate, monooleate or monoricinoleate, peanut oil, oily triglyceride mixtures of saturated vegetable fatty acids containing 8 to 12 carbon atoms or propylene glycGl esters, e.g.
propylene glycol monostearate.
The non-aggregate portion of the composition may contain further pharmaceutical carriers or diluents [component d)] which do not hinder the formation of the active agent- and emulsifier-containing aggregates or impair the stability of the resulting aggregates.
For example, it is convenient to add water-soluble solid or liquid physiologically tolerable mono-valent or polyvalent alcohols. Examples of suitablealcohols are: ethanol, propylene glycol, ylycerin, su~ar alcohols and polyethylene glycols having a mean molecular weight of, for example, 300 to 10000. An addition of polyalcohols, e.g. polyeth~lene glycol, which will pro-mote the solubilization of the active agents which aredifficultly soluble in water, is particularly desirable when the emulsifi.er mixture used contains no oxyethylen-oxy-propylene polymers or only small amounts thereof.
For the product.ion of liquid administration forms it is preferred to add liquid alcohols, e.g. lower mono-lQ57i96 valent or polyvalent alcohols and/or polyethylene glycols with mean molecular weights ~elow 2000, preferably bet-ween 300 and 1500. For solid medicinal preparations it is convenient to use alcohols which are solid at room temperature, e.g. sugar alcohol.s and/or polyethylene glycols having mean molecular weights over 1800, preferabl~-~etween 2000 and 10000, especially 5000-7000.

The porti.on of the composition comprising polyalcohols and emulsi.fiers may be cornposed of one ~ or several non emulsifying polyalcohols, preferably polyethylene ylycols, and one or several non-ionic tensides of the polyol fatty acid ester type, preferably polyoxyethylene-sorbitan fatty acid esters, and/or of the ethoxylated higher alcohol type, preferably ethoxyl.ated cholesterin, and/or d.ialkyl-sulphosuccinates, or may consist of polyalcohols having emulsifying properti.es, such as polyoxyethylene--polyoxypropylene polymers, optional].y ln adm.txture with one or several of thc-~ terlsides mentloned above and/or non-emulsiyiny polyalcohols. Especially suitable is a combination of ethoxylated cholesterin and poly~
ethylene ylycols and/or pol.yoxyetllylene-polyoxypropvlene polymers.

- 11 - 100~41~5 10~7~96 Water-containing compositions of the invention may contain between 20 % and ~5 e.g.up to 90 %, preferably between 30 ~ and 70 %, e.g. ~etween 30 and 50 % by ~teight of water and optionally further ad-juvants. The alcohol or polyol content of the aqueous liquid may, for example, be between 0 % and 50 ~, preferably between 20 ~ and 40 ~ by weight of the formulation.

Anhydrous liquid preparations may con-..ain the active agent-and emulsifier-containing aggregates finely distributed in a water-soluble and/or water dispersible liquid carrier material consisting of one or several liquid carriers and optionally further adjuvants. Suitable liquid car-cier materials are especially physiologically tolerable lower monovalent or polyvalent alcohols and/or liquid polye'chylene glycols, e.g. polyethylene glycols having mean mol~cular weights below 2000.

Liquid compositions may contain ~ as further components additional pharmaceutical adjuvants, e~g~ preserviny and flavouring agents and bu~fer materials. The liquid preparations may contain further physiologically tolerable water-soluble and/or ~ater-dispersible solid ma~erials, especially when they are to be wor~ed up into solid dosaye forms.
The solid medicinal preparations of the in-vention contain the active agent and emulsifier-containing aggregates finely distributed in a carrier material which is ormed from one or several water-soluble and/or water-dispersible solid materials and optionally further pharma-ceutical adjuvants.
5uitable physioloyically tolerable, water-soluble solid materials are, for example, polyethylene glycols which are solid at room temperature, preferably polyethylene glyco]s having a mean molecular weight between about 2000 and 10000, preferably between 6000 and 10000, polyvinyl pyrrolidones, excess solid oxy-ethylenoxy-propylene polymers, sugar~,e.cJ~ lacl:ose, sugar alcohols, e.g. ~annitol or sorbitol, and carboxy-methyl cellulose.
The solid materials dispersible in waterare preferably used in the form of finely dispersed powders which owing to their larye surface are capable of absorbing the finely distributed active agent- and emulsifier-containing aggregates~

lOS7196 Suitable solid materials are, for example, pnysiologically tolerable, in water dispersible, non-swelling inorganic and/or organic carrier materials, insofar as they do not irreversibly bind the active agents used. Suita~le inorganic carrier materials are, for example, dicalcium phosphates or highly dispersed silicic acids having a tapped volume preferably between 250 and 1000 cc,~00 g, especially wet precipitated silicic acid.
Depending on the desired formulation! the solid medicinal preparations may contain as further components additional physiologically tolerahle pharma-ceutical adju~ants, e.g. preserving and flavouring agents and any desired tabletting adjuvants generally used in the producti.on of tablets o.r any desired suppository r.lasses used in the production of supposi.tories.
The active agent-conLaining agyregates present --~ may have a diameter up to 20 000 A, preerably betw~ell 100 alld 10 000 ~, espec.icllly below 2000 A. or above 400 A~
In a~ueous medicinal preparations the distribution of the emulsifier~ and active ayent-containirlg aggregates in the aqueous liquid preferably is so fine that transparent or slightly opalescent liquids are ob-tained. The diameter of the active agent- and emulsi~

2~ fier~containing aggregates preferably is less than 2000, - 14 - 100-41~5 especially less than 1000 A.
The anhydrous solid or liquid compositions Of the invention are dried preparations or liquid preparations which contain the active agent-containing aggregates preferably so finely distributedthat when brought into an aqueous medium they rapidly give a transparent or slightly opalescent liquid, wherein the difficultly absorbable acti.ve agent or agents are solubilized in the form of finely distributed active agent- and emulsifier-containing aggregates.
The new compositions of the invention may be liquid or solid and are preferably ad-ministered orally. The liquid compositions of the inven-tion may, for example, be a~ninistered as a drop soluticn or s~rup. Anhydrous liquid compositions may also be filled lnto soft gelatin capsules or the production of unit-dose administrati.on forrns. T}le pre~erre~ water-containing compositions are drop solutions. Suit~ble solid administration forms are, for example, powders, granulates, capsules, tablets or film tablets fc;r oral adrnini~tration, or suppositories for rectal adrninistra-tion.

15 100 41~i A preferred form of the compositions of the invention are liquid or preferably solid galenic pre parations of ergot alkaloids or synthetic or semi-synthetic lysergic acid derivatives, wherein the total amount of polyalcohols and emulsifiers in the case of water-containing preparations preferably is between 15 % and 80 e.g.up to 70~ of the total formulation and in the case of anhydrous preparations between 40 and 99 ~ of the total formulation.
The compositions may be obtained by a process including the step of formulating aggregates havin~ at most a diameter of 20~000 A of components a) and b) as defined above.
The production of the liquid compositions may be effected in accordance with the invention by dispersing components a) and b) if desired with the addition of further pharmaceutlccll ad.jllvants, in the liquid carrier m~terlal, e.~. in an anhyd~ous rnedium or in water or in a water--containing medium, preferably using u].trasonic waves and/or high speed stirrers.

1057~96 In accordance with an embodiment of the process the active agents may first be dissolved with slight heating in the tensides, optionally with the addition of lipoid carrier materials and homogenized while treating with ultrasonic wave or high-speed stirrers.
The production of the solid compositions may also be effected in accordance with the invention by caxefully removing the liquid carrier materials, e.g.
water and/or lower alcohols, from primarily produced lLquid preparations and converting the resulting powdery or spongy porous dry preparation in known manner into the desired administration form.
The careful drying of the liquid preparations may be effected in known manner, e.g. by freeze-drying or spray-drying. For example, the liquid preparations may be frozen at temperatures between -80 and -50C and then lyophilized in a high vacuum, or the liquid pre-parations may be atomized in a drying chamber and dried by a warm air stream, e.g. at temperatures from 120 to 180C.
~f desired, the resulting dry preparations may subsequently be worked up in known manner, optionally with the addition of further suitable pharmaceutical ad-juvants such as tabletting adjuvants and suppository mass, e.g. filled into capsules, granulated, tabletted ~0S~'196 or moulded into suppositories.
In the following non-limitative Examples all temperatures are indicated in degrees Centigrade.
"Polytron" is a trade mark.

1 O 57~ 9 6 ~ 18 - 100-4195 EXAMPLES l - 30 Water-containing dro~ solutions of _______________ ____ _____________ difficultly absorbable active a~ents The formulations of Examples 1 - 28 having the composition indicated in the following Table 1, are produced as ollows:
The difficultly absorbable active agents are dissolved with slight heating (at temperatures bet-ween 30 and 50) in the emulsifiers and any lipoid carrier materials which may be present, optionally with the addition of part of the polyalcohols.
The water or an aqueous solution of any further adjuvants or a mixture of water and any poly-alcohols used is added to the above solution while stirring vigorously with a "Polytron" homogenizer, and the resulting mixture is homogenized for 5 to 6 minutes by treatment with ultrasonic wave and/or a "Polytron"
homogenizer The resulting homogenous liquids are filled into bottles fitted with droppers.

~057196 _ lg _ 100-4195 a) Solulan C 2 ~ of Ame~ican Cholesterol Comp.
b) Pluronic L 6 ~ " Wyandotte Chemicals c) " P 65~ " " "
d) " F 6 ~ " " "
e) Tween 6 ~ " Atlas Chemical Industries f) Myrj 52~ " " " "
g) Brij 56~ " " " "
h) Cremophor EL~ . " Badische Anilin- und Sodafabrik i) Cremophor AP~ " " " . " . "
j) Miglyol 81 ~ " Henkel k) Tegomuls 7 ~ " Goldschmidt AG
1) Tween 65~ " Atlas Chemical Indus~ries m) Aerosol OT~ " American Cyanamid Co.

105~196 100-4195 Table 1 Water-containing drop eolutions _, , . _ _ _ Example No. 1 2 3 4 5 6 7 8 . . ._ _ . _ _ mg of active agents:
Dihydroergocristine j 360 400 400 800 800 800 800 Dihydroergovaline 400 Dihydroergotoxine Dihydroergocornine Dihydroergocryptine Ergotamine 13-bromo-dihydroergotamine 13-bromo-dihydroergocryptine N,N-(2-methyl-4,5-dihydro-xyphenethyl)-hexamethylenediamine . . _. _ _ _ g of emulsifiers:
Cholesterin ethoxylated with ) 2.5 2.0 2.0 3.0 approx. 24 mols of ethylene oxide Oxy-ethylenoxy propylene polymer, 6.0 .0 1.5 13 12 mean molecular weight 2900bJ
Oxy-ethylenoxy-propylene polymer, mean molecular weight 3500C~
Oxy-ethylenoxy-propylene polymer~ 2.0 8 mean molecular weight 8700d) Polyoxyethylene-4-sorbitan 2.5 5 monostearate e) f ~
Polyoxyethylene-40-stearate ) ) 2.5 5 Polyoxyethylene-10-cetylic h~her Polyoxyethylene castor oil Polyeit)hylene glycol-400-stearate DAB7 1~
Polyethylelle-20-sorbitan triste~rate _ Sodium dioctyl sulphosuccinatem) _ _ __ .
g of lipoid carrier ma~erials:
.
Liquid triglyceride o~ saturated 0.9 1.8 1.8 3.5 3.5 fatty acids of 8-12 carbon atomsJ) Glycerin monolaurate k) 2.0 Glycerin monostearate palmitate 8 Glycerin monoricinoleate Glycerin monooleate Propylene glycol nonostearate Glycerin monomyristate Glycerin monoisostearate _ 1057~96 Table 1 Water-containing drop solutions Example No. 1 2 3 4 5 6 7 8 g of polyalcohols: .
Polyethylene glycol 300 20 20 40 40 Polyethylene glycol 400 .
Polyethylene glycol 600 -16 Polyethylene glycol 1500 10 18 40 Polyethylene glycol 2000 Glycerin _ l ___ g of further adjuvants:
Water 20 2015 27* 295 38.7 50.7 82.:

* Buffered to pH value 4.3 with a buffer mixture of sodium acetate/
acetic acid.

~057~96 - 22 - 100-4195 Table 1 _ Water-containing drop solutions Example No. 9 1 10 11 12 13 14 15 16 ;
_ _ _ mg of active agents:
Dihydroergocristine 80 Dihydroergovaline 800 800 800 Dihydroergotoxine 400 400 Dihydroergocornine 800 Dihydroergocryptine 600 Ergotamine 13-bromo-dihydroergotamine 13-bromo-dihydroergocryptine N.N-(2-methyl-4,5-dihydroxyphen-- ethyl)-hexamethylenediamine , ___ _ g of emulsifiers:
Cholesterin ethoxylated with 3 3 approx. 24 mols of ethylene oxide~) Oxy-ethylenoxy-propyiene 10 10 10 12 6 10 polymer, mean molecular weight 2900b) Oxy-ethylenoxy-propylene polymer, mean molecular weight 3500C) Oxy-ethylenoxy-propylene po~ymer 5 mean molecular weight 8700 J
Polyoxyethylene-4-sorbitan monostearate e) Polyoxyethylene-40-stearate Polyoxyethylene-10-cetylic ether g) Polyoxyethylene castor oilh) 10 5 Polyethylene gl~col-400-8 tearate DAB7 5 8 teYaraYte ~ ) 10 Sodium dioctyl sulphosuccinatem) . . .
_ __ . _ g of lipoid carrier materials:
Liquid triglyceride of satura- 1.0 1.5 ted fatty acids of 8-12 carbon atoms j) Glycerin monolaurate 5 Glycerin monostearate palmitatek) _ _ _ __ __ ~057196 .

Table 1 .
Water~containing drop solutionæ

. ! -- -- I _ ~ ~ .
Example No. 9 10 11 12 13 14 15 16 _ - __ _. _ . . _ _ . _, _ _ Glycerin monoricinoleate Glycerin monooleate Propylene glycol monosteara~e Glycerin monomyristate Glycerin monoisostearate _ _ __ ._ __ _ _ _ _.
g of polyalcohols:
Polyethylene glycol 300 40 40 45 40 40 Polyethylene glycol 400 40 Polyethylene glycol 600 5.5 Polyethylene glycol 1500 40 Polyethylene glycol 2000 Glycerin 28 _. . _ g of further adjuvants:
Water 34.2 39.2 39.2 44.2 71.6 I9.5 S4.2 42~9 *Buffered to pH value 4.3 with a buffer mixture of sodium acetate/
acetic acid.

1057~9~ - 24 - 100-4195 Table 1 Water-containing drop solutions Example No. 17 13 19 20 ~ 23 24 mg of active agents: _ _ _ .
Dihydroergocristine 400 400 400 200 200 800 200 Dihydroergovaline Dihydroergotoxine Dihydroergocornine Dihydroergocryp~ine Ergotamine 800 13-bromo-dihydroergotamine 13-bromo-dihydroergocryptine N,N-(2-methyl-4,5-dihydroxyphen-ethyl)-hexamethylenediamine g of emulsifiers:
Cholesterin ethoxylated with -approx.)24 mols of ethylene oxide a Oxy-ethylenoxy-propylene polymb~, mean molecular weight Oxy-ethylenoxy-propylene 8 po~ymer, mean molecular weight 3500C) Oxy-ethylenoxy-propylene polymer, mean molecular weight 8700d) .
Polyoxyethylene-4-sorbitan monostearate e) ,!
Polyoxyethylene-40-stearatef) Polyoxyethylene~10-cetylic ether &) Polyoxyethylene castor oilh) Polyethylene glycol-400-stearate DAB7 i) Polyethylene-20-sorbitan tristearate 1) Sodium dioctyl sulpho-succinate m) g of liPoid carrier materials _ Liquid triglyceride of saturated fatty acids of 8-12 carbon atoms j~ _ _ _ ~ns7~6 Table 1 ~ater-containing drop solutions __ , _ _ Example No. 7 l8 19 20 21 22 23 24 _ Glycerin monolaurate _ 2 _ -Glycerin mo~Qstearate palmitate J
Glycerin monoricinoleate 2 Glycerin monooleate ~ 1 Propylene glycol monostearate 1 Glycerin monomyristate 1 Glycerin monoisostearate 0.5 . . __ _ _ g of pc ~ alcohols Polyethylene glycol 300 Polyethylene glycol 400 Polyethylene glycol 600 40 Polyethylene glycol 1500 Polyethylene glycol 2000 Glycerin 10 _ _ g of further adjuvants:
Water 81 2 89 6 91.6 91.6 95.~ 95.8 53.2 96.8 1057~6 Table 1 Water-containing drop solutions Exa=ple No. 25 26 27 2829 30 .
_ ~
mg of active agents:
Dihydroergocristine 800 Dihydroergo~ine 600 Dihydroergotamine 300 Dihydroergocornine Dihydroergocryptine Ergotamine 13-bromo-dihydroergotamine 120 13-bromo-dihydroergocryptine 50 N,N-(2-methyl-4,5-dihydroxyphen- 80 ethyl)-hexamethylenediamine _ g of emulsifiers-Cholesterin ethoxylated with 3 5.8 5 6 3 approx )24 mols of ethylene oxide Oxy-ethylenoxy-propylene 2.25 polymb~, mean molecular weight Oxy-ethylenoxy-propylene polymer, mean molecular weight 3500C) Oxy-ethylenoxy-propylene l polyn~er~ ~an molecular .
weight 8700d) Polyoxyethylene-4-sorbitan monostearate e) Polyoxyethylene-40-stearatef~
Polyoxyethylene-10-cctylic .
ether g) Polyoxyethylene castor oilh) Polyethylene glycol-400-stearate DAB7 i) Polyethylene-20-sorbitan tristearate 1) Sodium dioctyl sulpho-succinate m) _ _ g of lipo d carrier materials Liquid triglyceride of 3.5 saturated fatty acids of 8-12 carbon atoms j) _ _ _ _ _ _ _ __ 10~7~96 Table 1 Water-containing drop solutions Example No. 25 26 27 28 29 3G

Glycerin monolaurate Glycerin mo~)ostearate palmitate Glycerin monoricinoleate Glycerin monooleate Propylene glycol monostearate Glycerin nomyristate Glycerin monoisostearate .. _ _ g of_polyalcohols Polyethylene glycol 300 45 47 25 Polyethylene glycol 400 3 30 Polyethylene glycol 600 Polyethylene glycol 1500 Polyethylene glycol 2000 . .
Glycerin _ _ _ ~
g of further adjuvants: 4647 3 40 50 4G , *Buffered to pH value 4.3 with a buffer mixture of sodium acetate~
scetic acid.

10~7196 ~XAMPLE 31: Dihydroer~otamlne-containin~ dro~ solution - 60 mg of dihydroergotamine mesylate are added together with 1.5 g of cholesterin ethoxylated with approx. 24 mols of ethylene oxide a) to 60 cc of water adjusted to pH 4.1 with a buffer mixture of sodium acetate/acetic acid, and homogenized with a "Polytron"
homogenizer. The clear liquid is filled into bottles fitted wi h droppers.
EXAMPLE 32: Dihydroer~otamine-containin~ anhydrous dro~ Solutions a) 2 g of dihydroergotamine are added together with 50 g of cholesterin ethoxylated with approx. 24 mols of ethylene oxide a) to 500 g of polyethylene glycol 400 while heating to 50 in a water bath, treatment is effected with ultrasonic waves for 5 minutes, and the resulting clear liquid is filled into bottles fitted with droppers.
b) The process ls effected as described ln section a) above, except that a mlxture of 250 g of polyethylene glycol 400 and 250 g of glycerin is used in place of 50 g of polyethylene glycol 400.
EXAMPLE 33: Dihvdroer~onine-containlnq soft ~elatin ca~sules

3 g of dihydroergonine are added together with 75 g of cholesterin ethoxylated with approx. 24 mols of ~OS7~9~
- ~9 - 100-4195 ethylene oxide a) to 150 cc of polyethylene glycol 300 while heating in a water bath of 50 and subjecting to ultrasonic waves. The clear liquid is subsequently filled into soft gelatin capsules in quantities of 100 mg/
capsule.
EXAMPLE 34: Dihydroer~ocristine-conta~ninq ca~sules 300 mg of dihydroergocristine are dissolved together with 1.7 g of cholesterin ethoxylated with approx. 24 mols of ethylene oxide aj and 1.2 g of glycerin monolaurate while heating to 40, and homogenized with the addition of 30 g of a 22% solution of oxy-ethylenoxy-propylene polymers having a mean molecular weight of 8700d) in water. After diluting with 50 cc of water, freezing is rapidly effected in a rotating flask at -80 and lyophilization is effected in a high vacuum. As lyophilization progresses the dry material is gradually heated to 25-30. The resulting dry preparation is subse~uently filled into capsules in quantities of 50 mg/
capsule.
EXAMPLE 35: Dihy~roer~otamine-containir~~ caEsules 30 mg of dihydroergotamine are dissolved together with 750 mg of cholesterin ethoxylated with approx. 24 mols of ethylene oxide a) in 50 cc of absolute ethanol, and the solution is evaporated to dryness in a vacuum at 30. The residue is homogenized with a'poly-.

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tron~homcgenizer for about 5 minutes while gradually adding 100 cc of distilled water. 225 mg of highly dis-persed silicic acid ) are suspended in the resulting clear liquid, and the suspension is homogenized by treatment with ultrasonic waves at 30 for 3 minutes.
The suspension is frozen at -80 and subsequently lyophilized. The lyophilized product is filled into gelatin capsules in quantities of lO0 mg/capsule.
EX~MPLE 36: Dihxdro r~ovaline-containin~ lyophilized E~roduct__n_freeze-dried tam~oules 400 mg of dihydroergovaline are dissolved together with 10 g of cholesterin ethoxylated with approx. 2~ mols of ethylene oxide a) and 40 g of polyethylene glycol 2000 in 300 cc of absolute ethanol.
lS The solution is evaporated to dryness in a rotary evaporator at 30. 200 cc o~ disti'led water are slcwly added to the residue while homogenized continually with the polytron homogenizer. The clear micellar solution of the active agent is illed into ampoules (2mg of dihydroergovaline per ampoule) and the ampoules are rapidly frozen at -80, lyophilized and sealed in a vacuum.
The dry preparations having the composition indicated in Table 2 may also be produced in a manner analogous to that described in Examples 34-36, and filled into capsules or dry ampoules or granulated and/
or tabletted with the addition of suitable galenic adjuvants:

n) Silicic acid K320 (tapped volume about 500 cc/lOO~g) of the firm Degussa o) Solulan C16 of the firm American Cholesterol Comp.
p) PVP K30 of the firm Badische Anilin- und Sodafabrik q) Primojel of the firm Scholten's Chemische Fabrieken N~V.

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Claims (7)

The embodiments of the invention in which an exclusive property is claimed are defined as follows:

1. A pharmaceutical composition comprising aggregates of diameter of at most 20,000 A, comprising component a) an ergot alkaloid, and component b) a pharmaceutically acceptable ethoxylated cholesterin emulsifier having an HLB value of from 10 to 30 and present in an amount greater than 10 times by weight of the ergot alkaloid.

2. A pharmaceutical composition according to claim 1, wherein the ergot alkaloid is chosen from dihydroergotoxine, dihydroergocristine, 13-bromodihydroergocristine, dihydro-ergonine, dihydroergocryptine, dihydroergotamine, 13-bromodihydroergotamine, dihydroergocornine and dihydro-ergovaline, and ergotamine.

3. A pharmaceutical composition according to claim 1, wherein the ergot alkaloid is dihydroergonine.

4. A pharmaceutical composition according to claim 1, wherein the ratio of component b) to component a) is from 10 to 1 to 50 to 1.

5. A pharmaceutical composition according to claim 1, wherein the ratio of component b) to component a) is from 12 to 1 to 25 to 1.

6. A pharmaceutical composition according to claim 1, wherein the ratio of component b) to component a) is 25 to 1.

7. A pharmaceutical composition according to claim 1, wherein component b) is cholesterin ethoxylated with approximately 24 moles of ethylene oxide per mole cholesterin.